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2. 2-Arylquinolines as novel anticancer agents with dual EGFR/FAK kinase inhibitory activity: synthesis, biological evaluation, and molecular modelling insights

Author

Elbadawi, Mostafa M, Eldehna, Wagdy M, El-Hafeez, Amer Ali Abd, Somaa, Warda R, Albohy, Amgad, Al-Rashood, Sara T, Agama, Keli K, Elkaeed, Eslam B, Ghosh, Pradipta, Pommier, Yves, and Abe, Manabu

Subjects
Medicinal and Biomolecular Chemistry, Chemical Sciences, Cancer, Antineoplastic Agents, Apoptosis, Cell Proliferation, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, ErbB Receptors, Focal Adhesion Kinase 1, Humans, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors, Quinolines, Structure-Activity Relationship, Tumor Cells, Cultured, Quinoline, anticancer, EGFR inhibitors, FAK inhibitors, molecular dynamics, Biochemistry and Cell Biology, Medicinal & Biomolecular Chemistry, Medicinal and biomolecular chemistry
Abstract

In this study, different assortments of 2-arylquinolines and 2,6-diarylquinolines have been developed. Recently, we have developed a new series of 6,7-dimethoxy-4-alkoxy-2-arylquinolines as Topoisomerase I (TOP1) inhibitors with potent anticancer activity. Utilising the SAR outputs from this study, we tried to enhance anticancer and TOP1 inhibitory activities. Though target quinolines demonstrated potent antiproliferative effect, specifically against colorectal cancer DLD-1 and HCT-116, they showed weak TOP1 inhibition which may be attributable to their non-coplanarity. Thereafter, screening against kinase panel revealed their dual inhibitory activity against EGFR and FAK. Quinolines 6f, 6h, 6i, and 20f were the most potent EGFR inhibitors (IC50s = 25.39, 20.15, 22.36, and 24.81 nM, respectively). Meanwhile, quinolines 6f, 6h, 6i, 16d, and 20f exerted the best FAK inhibition (IC50s = 22.68, 14.25, 18.36, 17.36, and 15.36 nM, respectively). Finally, molecular modelling was employed to justify the promising EGFR/FAK inhibition. The study outcomes afforded the first reported quinolines with potent EGFR/FAK dual inhibition.

Published
2022

5. Topoisomerase I-driven repair of UV-induced damage in NER-deficient cells

Author

Saha, Liton Kumar, Wakasugi, Mitsuo, Akter, Salma, Prasad, Rajendra, Wilson, Samuel H., Shimizu, Naoto, Sasanuma, Hiroyuki, Huang, Shar-yin Naomi, Agama, Keli, Pommier, Yves, Matsunaga, Tsukasa, Hirota, Kouji, Iwai, Shigenori, Nakazawa, Yuka, Ogi, Tomoo, and Takeda, Shunichi

Published
2020

11. TOP1-DNA Trapping by Exatecan and Combination Therapy with ATR Inhibitor

Author

Jo, Ukhyun, primary, Murai, Yasuhisa, additional, Agama, Keli K., additional, Sun, Yilun, additional, Saha, Liton Kumar, additional, Yang, Xi, additional, Arakawa, Yasuhiro, additional, Gayle, Sophia, additional, Jones, Kelli, additional, Paralkar, Vishwas, additional, Sundaram, Ranjini K., additional, Van Doorn, Jinny, additional, Vasquez, Juan C., additional, Bindra, Ranjit S., additional, Choi, Woo Suk, additional, and Pommier, Yves, additional

Published
2022
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12. 2-Arylquinolines as novel anticancer agents with dual EGFR/FAK kinase inhibitory activity: synthesis, biological evaluation, and molecular modelling insights

Author

Elbadawi, Mostafa M., primary, Eldehna, Wagdy M., additional, Abd El-Hafeez, Amer Ali, additional, Somaa, Warda R., additional, Albohy, Amgad, additional, Al-Rashood, Sara T., additional, Agama, Keli K., additional, Elkaeed, Eslam B., additional, Ghosh, Pradipta, additional, Pommier, Yves, additional, and Abe, Manabu, additional

Published
2021
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13. From Antarctica to cancer research: a novel human DNA topoisomerase IB inhibitor from Antarctic sponge Dendrilla antarctica.

Author

Ottaviani, Alessio, Welsch, Joshua, Agama, Keli, Pommier, Yves, Desideri, Alessandro, Baker, Bill J., and Fiorani, Paola

Subjects
DNA topoisomerase I, HUMAN DNA, DNA topoisomerase inhibitors, DNA-binding proteins, CANCER research, HUMAN experimentation
Abstract

Nature has been always a great source of possible lead compounds to develop new drugs against several diseases. Here we report the identification of a natural compound, membranoid G, derived from the Antarctic sponge Dendrilla antarctica displaying an in vitro inhibitory activity against human DNA topo-isomerase 1B. The experiments indicate that membranoid G, when pre-incubated with the enzyme, strongly and irreversibly inhibits the relaxation of supercoiled DNA. This compound completely inhibits the cleavage step of the enzyme catalytic mechanism by preventing protein binding to the DNA. Membranoid G displays also a cytotoxic effect on tumour cell lines, suggesting its use as a possible lead compound to develop new anticancer drugs. [ABSTRACT FROM AUTHOR]

Published
2022
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21. Mitochondrial tyrosyl‐ DNA phosphodiesterase 2 and its TDP 2 S short isoform

Author

Huang, Shar‐yin N, primary, Dalla Rosa, Ilaria, additional, Michaels, Stephanie A, additional, Tulumello, David V, additional, Agama, Keli, additional, Khiati, Salim, additional, Jean, Sae Rin, additional, Baechler, Simone A, additional, Factor, Valentina M, additional, Varma, Sudhir, additional, Murai, Junko, additional, Miller Jenkins, Lisa M, additional, Kelley, Shana O, additional, and Pommier, Yves, additional

Published
2018
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22. ALC1/CHD1L, a chromatin-remodeling enzyme, is required for efficient base excision repair

Author

00706707, 80362531, 90711143, 60188191, Tsuda, Masataka, Cho, Kosai, Ooka, Masato, Shimizu, Naoto, Watanabe, Reiko, Yasui, Akira, Nakazawa, Yuka, Ogi, Tomoo, Harada, Hiroshi, Agama, Keli, Nakamura, Jun, Asada, Ryuta, Fujiike, Haruna, Sakuma, Tetsushi, Yamamoto, Takashi, Murai, Junko, Hiraoka, Masahiro, Koike, Kaoru, Pommier, Yves, Takeda, Shunichi, Hirota, Kouji, 00706707, 80362531, 90711143, 60188191, Tsuda, Masataka, Cho, Kosai, Ooka, Masato, Shimizu, Naoto, Watanabe, Reiko, Yasui, Akira, Nakazawa, Yuka, Ogi, Tomoo, Harada, Hiroshi, Agama, Keli, Nakamura, Jun, Asada, Ryuta, Fujiike, Haruna, Sakuma, Tetsushi, Yamamoto, Takashi, Murai, Junko, Hiraoka, Masahiro, Koike, Kaoru, Pommier, Yves, Takeda, Shunichi, and Hirota, Kouji

Abstract

ALC1/CHD1L is a member of the SNF2 superfamily of ATPases carrying a macrodomain that binds poly(ADP-ribose). Poly(ADP-ribose) polymerase (PARP) 1 and 2 synthesize poly(ADP-ribose) at DNA-strand cleavage sites, promoting base excision repair (BER). Although depletion of ALC1 causes increased sensitivity to various DNA-damaging agents H₂O₂, UV, and phleomycin), the role played by ALC1 in BER has not yet been established. To explore this role, as well as the role of ALC1’s ATPase activity in BER, we disrupted the ALC1 gene and inserted the ATPase-dead (E165Q) mutation into the ALC1 gene in chicken DT40 cells, which do not express PARP2. The resulting ALC1⁻/⁻ and ALC1⁻/E165Q cells displayed an indistinguishable hypersensitivity to methylmethane sulfonate (MMS), an alkylating agent, and to H₂O₂, indicating that ATPase plays an essential role in the DNA-damage response. PARP1⁻/⁻ and ALC⁻/⁻/PARP1⁻/⁻ cells exhibited a very similar sensitivity to MMS, suggesting that ALC1 and PARP1 collaborate in BER. Following pulse-exposure to H₂O₂, PARP1⁻/⁻ and ALC1⁻/⁻/PARP1⁻/⁻ cells showed similarly delayed kinetics in the repair of single-strand breaks, which arise as BER intermediates. To ascertain ALC1’s role in BER in mammalian cells, we disrupted the ALC1 gene in human TK6 cells. Following exposure to MMS and to H₂O₂, the ALC⁻/⁻ TK6 cell line showed a delay in single-strand-break repair. We therefore conclude that ALC1 plays a role in BER. Following exposure to H₂O₂, ALC⁻/⁻ cells showed compromised chromatin relaxation. We thus propose that ALC1 is a unique BER factor that functions in a chromatin context, most likely as a chromatin-remodeling enzyme.

Published
2017

23. ALC1/CHD1L, chromatin-remodeling enzyme, is required for efficient base excision repair

Author

Tsuda, Masataka, Cho, Kosai, Ooka, Masato, Shimizu, Naoto, Watanabe, Reiko, Yasui, Akira, Nakazawa, Yuka, Ogi, Tomoo, Harada, Hiroshi, Agama, Keli, Nakamura, Jun, Asada, Ryuta, Fujiike, Haruna, Sakuma, Tetsushi, Yamamoto, Takashi, Murai, Junko, Hiraoka, Masahiro, Koike, Kaoru, Pommier, Yves, Takeda, Shunichi, Hirota, Kouji, Tsuda, Masataka, Cho, Kosai, Ooka, Masato, Shimizu, Naoto, Watanabe, Reiko, Yasui, Akira, Nakazawa, Yuka, Ogi, Tomoo, Harada, Hiroshi, Agama, Keli, Nakamura, Jun, Asada, Ryuta, Fujiike, Haruna, Sakuma, Tetsushi, Yamamoto, Takashi, Murai, Junko, Hiraoka, Masahiro, Koike, Kaoru, Pommier, Yves, Takeda, Shunichi, and Hirota, Kouji

Abstract

type:text, ALC1/CHD1L is a member of the SNF2 superfamily of ATPases carrying a macrodomain that binds poly(ADP-ribose). Poly(ADP-ribose) polymerase (PARP) 1 and 2 synthesize poly(ADP-ribose) at DNA-strand cleavage sites, promoting base excision repair (BER). Although depletion of ALC1 causes increased sensitivity to various DNA-damaging agents (H2O2, UV, and phleomycin), the role played by ALC1 in BER has not yet been established. To explore this role, as well as the role of ALC1’s ATPase activity in BER, we disrupted the ALC1 gene and inserted the ATPase-dead (E165Q) mutation into the ALC1 gene in chicken DT40 cells, which do not express PARP2. The resulting ALC1-/- and ALC1-/E165Q cells displayed an indistinguishable hypersensitivity to methylmethane sulfonate (MMS), an alkylating agent, and to H2O2, indicating that ATPase plays an essential role in the DNA-damage response. PARP1-/- and ALC1-/-/PARP1-/- cells exhibited a very similar sensitivity to MMS, suggesting that ALC1 and PARP1 collaborate in BER. Following pulse-exposure to H2O2, PARP1-/- and ALC1-/-/PARP1-/- cells showed similarly delayed kinetics in the repair of single-strand breaks, which arise as BER intermediates. To ascertain ALC1’s role in BER in mammalian cells, we disrupted the ALC1 gene in human TK6 cells. Following exposure to MMS and to H2O2, the ALC1-/- TK6 cell line showed a delay in single-strand-break repair. We therefore conclude that ALC1 plays a role in BER. Following exposure to H2O2, ALC1-/- cells showed compromised chromatin relaxation. We thus propose that ALC1 is a unique BER factor that functions in a chromatin context, most likely as a chromatin-remodeling enzyme., This work was supported by the JSPS KAKENHI Grant Number (JP16K12598, JP16H02957 and JP16H01314 to KH, JP16H06306 to ST and JP16J02252 to RA), the JSPS Core-to-Core Program (A) Advanced Research Networks (to ST), the Takeda Science Foundation and Yamada Science Foundation (to KH), and the Center for Cancer Research, Intramural Program of the US National Cancer Institute (Z01 BC 006150 to KA and YP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Published
2017

24. ALC1/CHD1L, a chromatin-remodeling enzyme, is required for efficient base excision repair

Author

Tsuda, Masataka, primary, Cho, Kosai, additional, Ooka, Masato, additional, Shimizu, Naoto, additional, Watanabe, Reiko, additional, Yasui, Akira, additional, Nakazawa, Yuka, additional, Ogi, Tomoo, additional, Harada, Hiroshi, additional, Agama, Keli, additional, Nakamura, Jun, additional, Asada, Ryuta, additional, Fujiike, Haruna, additional, Sakuma, Tetsushi, additional, Yamamoto, Takashi, additional, Murai, Junko, additional, Hiraoka, Masahiro, additional, Koike, Kaoru, additional, Pommier, Yves, additional, Takeda, Shunichi, additional, and Hirota, Kouji, additional

Published
2017
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27. Characterization of DNA topoisomerase I in three SN-38 resistant human colon cancer cell lines reveals a new pair of resistance-associated mutations

Author

Jensen, Niels Frank, Agama, Keli, Roy, Amit, Smith, David Hersi, Pfister, Thomas D, Rømer, Maria Unni, Zhang, Hong-Liang, Doroshow, James H, Knudsen, Birgitta R., Stenvang, Jan, Brünner, Nils, Pommier, Yves, Jensen, Niels Frank, Agama, Keli, Roy, Amit, Smith, David Hersi, Pfister, Thomas D, Rømer, Maria Unni, Zhang, Hong-Liang, Doroshow, James H, Knudsen, Birgitta R., Stenvang, Jan, Brünner, Nils, and Pommier, Yves

Abstract

Background: DNA topoisomerase I (Top1) is a DNA unwinding protein and the specific target of the camptothecin class of chemotherapeutic drugs. One of these, irinotecan, acting through its active metabolite SN-38, is used in the treatment of metastatic colorectal cancer. However, resistance to irinotecan represents a major clinical problem. Since molecular alterations in Top1 may result in resistance to irinotecan, we characterized Top1 in three human colon cancer cell lines with acquired resistance to SN-38. Methods: Three SN-38 resistant (20–67 fold increased resistance) cell lines were generated and compared to wildtype parental cells with regards to: TOP1 gene copy number and gene sequence, Top1 expression (mRNA and protein), Top1 enzymatic activity in the absence and presence of drug, and Top1-DNA cleavage complexes in drug treated cells. TOP1 mutations were validated by PCR using mutant specific primers. Furthermore, cross-resistance to two indenoisoquinoline Top1-targeting drugs (NSC 725776 and NSC 743400) and two Top2-targeting drugs (epirubicin and etoposide) was investigated. Results: Two of three SN-38 resistant cell lines carried TOP1 gene copy number aberrations: A TOP1 gene copy gain and a loss of chromosome 20, respectively. One resistant cell line harbored a pair of yet unreported TOP1 mutations (R364K and G717R) in close proximity to the drug binding site. Mutant TOP1 was expressed at a markedly higher level than wild-type TOP1. None or very small reductions were observed in Top1 expression or Top1 activity in the absence of drug. In all three SN-38 resistant cell lines Top1 activity was maintained in the presence of high concentrations of SN-38. None or only partial cross-resistance were observed for etoposide and epirubicin, respectively. SN-38 resistant cells with wild-type TOP1 remained sensitive to NSC 743400, while cells with mutant TOP1 was fully cross-resistant to both indenoisoquinolines. Top1-DNA cleavage c

Published
2016

28. Characterization of DNA topoisomerase I in three SN-38 resistant human colon cancer cell lines reveals a new pair of resistance-associated mutations

Author

Jensen, Niels Frank, primary, Agama, Keli, additional, Roy, Amit, additional, Smith, David Hersi, additional, Pfister, Thomas D., additional, Rømer, Maria Unni, additional, Zhang, Hong-Liang, additional, Doroshow, James H., additional, Knudsen, Birgitta R., additional, Stenvang, Jan, additional, Brünner, Nils, additional, and Pommier, Yves, additional

Published
2016
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29. Analogs of the novel phytohormone, strigolactone, trigger apoptosis and synergize with PARP inhibitors by inducing DNA damage and inhibiting DNA repair

Author

Croglio, Michael P., primary, Haake, Jefferson M., additional, Ryan, Colin P., additional, Wang, Victor S., additional, Lapier, Jennifer, additional, Schlarbaum, Jamie P., additional, Dayani, Yaron, additional, Artuso, Emma, additional, Prandi, Cristina, additional, Koltai, Hinanit, additional, Agama, Keli, additional, Pommier, Yves, additional, Chen, Yu, additional, Tricoli, Lucas, additional, LaRocque, Jeannine R., additional, Albanese, Christopher, additional, and Yarden, Ronit I., additional

Published
2016
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30. Mitochondrial tyrosyl-DNA phosphodiesterase 2 and its TDP2S short isoform.

Author

Huang, Shar-yin N., Rosa, Ilaria Dalla, Michaels, Stephanie A., Tulumello, David V., Agama, Keli, Khiati, Salim, Jean, Sae Rin, Baechler, Simone A., Factor, Valentina M., Varma, Sudhir, Murai, Junko, Jenkins, Lisa M. Miller, Kelley, Shana O., and Pommier, Yves

Abstract

Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs abortive topoisomerase II cleavage complexes. Here, we identify a novel short isoform of TDP2 (TDP2S) expressed from an alternative transcription start site. TDP2S contains a mitochondrial targeting sequence, contributing to its enrichment in the mitochondria and cytosol, while full-length TDP2 contains a nuclear localization signal and the ubiquitin-associated domain in the N-terminus. Our study reveals that both TDP2 isoforms are present and active in the mitochondria. Comparison of isogenic wild-type (WT) and TDP2 knockout (TDP2-/-/-) DT40 cells shows that TDP2-/-/- cells are hypersensitive to mitochondrial-targeted doxorubicin (mtDox), and that complementing TDP2-/-/- cells with human TDP2 restores resistance to mtDox. Furthermore, mtDox selectively depletes mitochondrial DNA in TDP2-/-/- cells. Using CRISPR-engineered human cells expressing only the TDP2S isoform, we show that TDP2S also protects human cells against mtDox. Finally, lack of TDP2 in the mitochondria reduces the mitochondria transcription levels in two different human cell lines. In addition to identifying a novel TDP2S isoform, our report demonstrates the presence and importance of both TDP2 isoforms in the mitochondria. [ABSTRACT FROM AUTHOR]

Published
2018
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33. Characterization of DNA topoisomerase I in three SN-38 resistant human colon cancer cell lines reveals a new pair of resistanceassociated mutations.

Author

Jensen, Niels Frank, Agama, Keli, Roy, Amit, Smith, David Hersi, Pfister, Thomas D., Rømer, Maria Unni, Hong-Liang Zhang, Doroshow, James H., Knudsen, Birgitta R., Stenvang, Jan, Brünner, Nils, and Pommier, Yves

Subjects
*DNA topoisomerases, *GENETICS of colon cancer, *CANCER cells, *GENETIC mutation, *MOLECULAR oncology, *MESSENGER RNA
Abstract

Background: DNA topoisomerase I (Top1) is a DNA unwinding protein and the specific target of the camptothecin class of chemotherapeutic drugs. One of these, irinotecan, acting through its active metabolite SN-38, is used in the treatment of metastatic colorectal cancer. However, resistance to irinotecan represents a major clinical problem. Since molecular alterations in Top1 may result in resistance to irinotecan, we characterized Top1 in three human colon cancer cell lines with acquired resistance to SN-38. Methods: Three SN-38 resistant (20-67 fold increased resistance) cell lines were generated and compared to wildtype parental cells with regards to: TOP1 gene copy number and gene sequence, Top1 expression (mRNA and protein), Top1 enzymatic activity in the absence and presence of drug, and Top1-DNA cleavage complexes in drug treated cells. TOP1 mutations were validated by PCR using mutant specific primers. Furthermore, cross-resistance to two indenoisoquinoline Top1-targeting drugs (NSC 725776 and NSC 743400) and two Top2-targeting drugs (epirubicin and etoposide) was investigated. Results: Two of three SN-38 resistant cell lines carried TOP1 gene copy number aberrations: A TOP1 gene copy gain and a loss of chromosome 20, respectively. One resistant cell line harbored a pair of yet unreported TOP1 mutations (R364K and G717R) in close proximity to the drug binding site. Mutant TOP1 was expressed at a markedly higher level than wild-type TOP1. None or very small reductions were observed in Top1 expression or Top1 activity in the absence of drug. In all three SN-38 resistant cell lines Top1 activity was maintained in the presence of high concentrations of SN-38. None or only partial cross-resistance were observed for etoposide and epirubicin, respectively. SN-38 resistant cells with wild-type TOP1 remained sensitive to NSC 743400, while cells with mutant TOP1 was fully cross-resistant to both indenoisoquinolines. Top1-DNA cleavage complex formation following drug treatment supported the other findings. Conclusions: This study adds to the growing knowledge about resistance mechanisms for Top1-targeting chemotherapeutic drugs. Importantly, two yet unreported TOP1 mutations were identified, and it was underlined that cross-resistance to the new indenoisoquinoline drugs depends on the specific underlying molecular mechanism of resistance to SN-38. [ABSTRACT FROM AUTHOR]

Published
2016
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37. Abstract A46: A novel immunoassay (ELISA) for quantitative gamma-H2AX detection and pharmacodynamic monitoring of DNA damage induced by chemotherapeutic agents and PARP inhibitors.

Author

Ji, Jay, primary, Zhang, Yiping, additional, Kinders, Robert, additional, Redon, Christophe, additional, Solier, Stephanie, additional, Agama, Keli, additional, Pommier, Yves, additional, Bonner, William, additional, Hollingshead, Melinda, additional, Rubinstein, Larry, additional, Chen, Alice, additional, Kummar, Shivaani, additional, Parchment, Ralph E., additional, Tomaszewski, Joseph E., additional, and Doroshow, James H., additional

Published
2011
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41. Collaborative Action of Brca1 and CtIP in Elimination of Covalent Modifications from Double-Strand Breaks to Facilitate Subsequent Break Repair

Author

Nakamura, Kyoko, primary, Kogame, Toshiaki, additional, Oshiumi, Hiroyuki, additional, Shinohara, Akira, additional, Sumitomo, Yoshiki, additional, Agama, Keli, additional, Pommier, Yves, additional, Tsutsui, Kimiko M., additional, Tsutsui, Ken, additional, Hartsuiker, Edgar, additional, Ogi, Tomoo, additional, Takeda, Shunichi, additional, and Taniguchi, Yoshihito, additional

Published
2010
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42. Topoisomerase I levels in the NCI-60 cancer cell line panel determined by validated ELISA and microarray analysis and correlation with indenoisoquinoline sensitivity

Author

Pfister, Thomas D., primary, Reinhold, William C., additional, Agama, Keli, additional, Gupta, Shalu, additional, Khin, Sonny A., additional, Kinders, Robert J., additional, Parchment, Ralph E., additional, Tomaszewski, Joseph E., additional, Doroshow, James H., additional, and Pommier, Yves, additional

Published
2009
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46. Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance

Author

Antony, Smitha, primary, Agama, Keli K., additional, Miao, Ze-Hong, additional, Takagi, Kazutaka, additional, Wright, Mollie H., additional, Robles, Ana I., additional, Varticovski, Lyuba, additional, Nagarajan, Muthukaman, additional, Morrell, Andrew, additional, Cushman, Mark, additional, and Pommier, Yves, additional

Published
2007
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50. Rif1 provides a new DNA-binding interface for the Bloom syndrome complex to maintain normal replication.

Author

Dongyi Xu, Muniandy, Parameswary, Leo, Elisabetta, Jinhu Yin, Thangavel, Saravanabhavan, Xi Shen, Ii, Miki, Agama, Keli, Rong Guo, Fox, III, David, Meetei, Amom Ruhikanta, Wilson, Lauren, Nguyen, Huy, Weng, Nan-ping, Brill, Steven J., Lei Li, Vindigni, Alessandro, Pommier, Yves, Seidman, Michael, and Weidong Wang

Subjects
RNA polymerases, DNA, VERTEBRATES, DEOXYRIBOSE, RNA
Abstract

BLM, the helicase defective in Bloom syndrome, is part of a multiprotein complex that protects genome stability. Here, we show that Rif1 is a novel component of the BLM complex and works with BLM to promote recovery of stalled replication forks. First, Rif1 physically interacts with the BLM complex through a conserved C-terminal domain, and the stability of Rif1 depends on the presence of the BLM complex. Second, Rif1 and BLM are recruited with similar kinetics to stalled replication forks, and the Rif1 recruitment is delayed in BLM-deficient cells. Third, genetic analyses in vertebrate DT40 cells suggest that BLM and Rif1 work in a common pathway to resist replication stress and promote recovery of stalled forks. Importantly, vertebrate Rif1 contains a DNA-binding domain that resembles the αCTD domain of bacterial RNA polymerase α; and this domain preferentially binds fork and Holliday junction (HJ) DNA in vitro and is required for Rif1 to resist replication stress in vivo. Our data suggest that Rif1 provides a new DNA-binding interface for the BLM complex to restart stalled replication forks. [ABSTRACT FROM AUTHOR]

Published
2010
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