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17 results on '"Krishnan, Rehna"'

2. In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor–microenvironment interactions

Author

Su, Peiran, Liu, Yin, Chen, Tianyi, Xue, Yibo, Zeng, Yong, Zhu, Guanghui, Chen, Sujun, Teng, Mona, Ci, Xinpei, Guo, Mengdi, He, Michael Y., Hao, Jun, Chu, Vivian, Xu, Wenxi, Wang, Shiyan, Mehdipour, Parinaz, Xu, Xin, Marhon, Sajid A., Soares, Fraser, Pham, Nhu-An, Wu, Bell Xi, Her, Peter Hyunwuk, Feng, Shengrui, Alshamlan, Najd, Khalil, Maryam, Krishnan, Rehna, Yu, Fangyou, Chen, Chang, Burrows, Francis, Hakem, Razqallah, Lupien, Mathieu, Harding, Shane, Lok, Benjamin H., O’Brien, Catherine, Berlin, Alejandro, De Carvalho, Daniel D., Brooks, David G., Schramek, Daniel, Tsao, Ming-Sound, and He, Housheng Hansen

Published
2024
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6. RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells

Author

Krishnan, Rehna, primary, Lapierre, Mariah, additional, Gautreau, Brandon, additional, Nixon, Kevin C J, additional, El Ghamrasni, Samah, additional, Patel, Parasvi S, additional, Hao, Jun, additional, Yerlici, V Talya, additional, Guturi, Kiran Kumar Naidu, additional, St-Germain, Jonathan, additional, Mateo, Francesca, additional, Saad, Amine, additional, Algouneh, Arash, additional, Earnshaw, Rebecca, additional, Shili, Duan, additional, Seitova, Alma, additional, Miller, Joshua, additional, Khosraviani, Negin, additional, Penn, Adam, additional, Ho, Brandon, additional, Sanchez, Otto, additional, Hande, M Prakash, additional, Masson, Jean-Yves, additional, Brown, Grant W, additional, Alaoui-Jamali, Moulay, additional, Reynolds, John J, additional, Arrowsmith, Cheryl, additional, Raught, Brian, additional, Pujana, Miguel A, additional, Mekhail, Karim, additional, Stewart, Grant S, additional, Hakem, Anne, additional, and Hakem, Razqallah, additional

Published
2023
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7. Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers

Author

Patel, Parasvi S, primary, Algouneh, Arash, additional, Krishnan, Rehna, additional, Reynolds, John J, additional, Nixon, Kevin C J, additional, Hao, Jun, additional, Lee, Jihoon, additional, Feng, Yue, additional, Fozil, Chehronai, additional, Stanic, Mia, additional, Yerlici, Talya, additional, Su, Peiran, additional, Soares, Fraser, additional, Liedtke, Elisabeth, additional, Prive, Gil, additional, Baider, Gary D, additional, Pujana, Miquel Angel, additional, Mekhail, Karim, additional, He, Housheng Hansen, additional, Hakem, Anne, additional, Stewart, Grant S, additional, and Hakem, Razqallah, additional

Published
2023
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8. RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells

Author

Krishnan, Rehna, Lapierre, Mariah, Gautreau, Brandon, Nixon, Kevin C.J., El Ghamrasni, Samah, Patel, Parasvi S., Hao, Jun, Yerlici, V. Talya, Guturi, Kiran Kumar Naidu, St-Germain, Jonathan, Mateo, Francesca, Saad, Amine, Algouneh, Arash, Earnshaw, Rebecca, Shili, Duan, Seitova, Alma, Miller, Joshua, Khosraviani, Negin, Penn, Adam, Ho, Brandon, Sanchez, Otto, Hande, M. Prakash, Masson, Jean Yves, Brown, Grant W., Alaoui-Jamali, Moulay, Reynolds, John J., Arrowsmith, Cheryl, Raught, Brian, Pujana, Miguel A., Mekhail, Karim, Stewart, Grant S., Hakem, Anne, Hakem, Razqallah, Krishnan, Rehna, Lapierre, Mariah, Gautreau, Brandon, Nixon, Kevin C.J., El Ghamrasni, Samah, Patel, Parasvi S., Hao, Jun, Yerlici, V. Talya, Guturi, Kiran Kumar Naidu, St-Germain, Jonathan, Mateo, Francesca, Saad, Amine, Algouneh, Arash, Earnshaw, Rebecca, Shili, Duan, Seitova, Alma, Miller, Joshua, Khosraviani, Negin, Penn, Adam, Ho, Brandon, Sanchez, Otto, Hande, M. Prakash, Masson, Jean Yves, Brown, Grant W., Alaoui-Jamali, Moulay, Reynolds, John J., Arrowsmith, Cheryl, Raught, Brian, Pujana, Miguel A., Mekhail, Karim, Stewart, Grant S., Hakem, Anne, and Hakem, Razqallah

Abstract

Breast cancer linked with BRCA1/2 mutations commonly recur and resist current therapies, including PARP inhibitors. Given the lack of effective targeted therapies for BRCA1-mutant cancers, we sought to identify novel targets to selectively kill these cancers. Here, we report that loss of RNF8 significantly protects Brca1-mutant mice against mammary tumorigenesis. RNF8 deficiency in human BRCA1-mutant breast cancer cells was found to promote R-loop accumulation and replication fork instability, leading to increased DNA damage, senescence, and synthetic lethality. Mechanistically, RNF8 interacts with XRN2, which is crucial for transcription termination and R-loop resolution. We report that RNF8 ubiquitylates XRN2 to facilitate its recruitment to R-loop-prone genomic loci and that RNF8 deficiency in BRCA1-mutant breast cancer cells decreases XRN2 occupancy at R-loop-prone sites, thereby promoting R-loop accumulation, transcription-replication collisions, excessive genomic instability, and cancer cell death. Collectively, our work identifies a synthetic lethal interaction between RNF8 and BRCA1, which is mediated by a pathological accumulation of R-loops.

Published
2023

9. Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers

Author

Patel, Parasvi S, Algouneh, Arash, Krishnan, Rehna, Reynolds, John J, Nixon, Kevin C J, Hao, Jun, Lee, Jihoon, Feng, Yue, Fozil, Chehronai, Stanic, Mia, Yerlici, Talya, Su, Peiran, Soares, Fraser, Liedtke, Elisabeth, Prive, Gil, Baider, Gary D, Pujana, Miquel Angel, Mekhail, Karim, He, Housheng Hansen, Hakem, Anne, Stewart, Grant S, Hakem, Razqallah, Patel, Parasvi S, Algouneh, Arash, Krishnan, Rehna, Reynolds, John J, Nixon, Kevin C J, Hao, Jun, Lee, Jihoon, Feng, Yue, Fozil, Chehronai, Stanic, Mia, Yerlici, Talya, Su, Peiran, Soares, Fraser, Liedtke, Elisabeth, Prive, Gil, Baider, Gary D, Pujana, Miquel Angel, Mekhail, Karim, He, Housheng Hansen, Hakem, Anne, Stewart, Grant S, and Hakem, Razqallah

Abstract

BRCA1 mutations are associated with increased breast and ovarian cancer risk. BRCA1-mutant tumors are high-grade, recurrent, and often become resistant to standard therapies. Herein, we performed a targeted CRISPR-Cas9 screen and identified MEPCE, a methylphosphate capping enzyme, as a synthetic lethal interactor of BRCA1. Mechanistically, we demonstrate that depletion of MEPCE in a BRCA1-deficient setting led to dysregulated RNA polymerase II (RNAPII) promoter-proximal pausing, R-loop accumulation, and replication stress, contributing to transcription-replication collisions. These collisions compromise genomic integrity resulting in loss of viability of BRCA1-deficient cells. We also extend these findings to another RNAPII-regulating factor, PAF1. This study identifies a new class of synthetic lethal partners of BRCA1 that exploit the RNAPII pausing regulation and highlight the untapped potential of transcription-replication collision-inducing factors as unique potential therapeutic targets for treating cancers associated with BRCA1 mutations.

Published
2023

13. Leucine Zipper Down-regulated in Cancer-1 (LDOC1) interacts with Guanine nucleotide binding protein-like 3-like (GNL3L) to modulate Nuclear Factor-kappa B (NF-κB) signaling during cell proliferation

Author

Indu Jose Thoompumkal, Kumaraswamy Anbarasu, Krishnan Rehna, and Sundarasamy Mahalingam

Subjects
0301 basic medicine, Cell signaling, Leucine zipper, Transcription, Genetic, Down-Regulation, Apoptosis, GTPase, Biology, Models, Biological, 03 medical and health sciences, 0302 clinical medicine, GTP-Binding Proteins, Cell Line, Tumor, Report, Humans, Protein Interaction Domains and Motifs, Phosphorylation, Nuclear protein, Molecular Biology, Cell Proliferation, Protein Stability, Cell growth, Tumor Suppressor Proteins, NF-kappa B, Transcription Factor RelA, Nuclear Proteins, Cell Biology, NFKB1, Molecular biology, Cell biology, Gene Expression Regulation, Neoplastic, HEK293 Cells, 030104 developmental biology, 030220 oncology & carcinogenesis, Ectopic expression, Signal transduction, Protein Binding, Signal Transduction, Developmental Biology
Abstract

Guanine nucleotide binding protein-like 3-like (GNL3L) is an evolutionarily conserved putative nucleolar GTPase belonging to the HSR1-MMR1 family. In the present study, using protein-protein interaction assays, we show that Leucine Zipper Down-regulated in Cancer-1 (LDOC1) is a novel interacting partner of GNL3L. Furthermore, our results reveal that ectopic expression of LDOC1 destabilizes endogenous GNL3L levels and down modulates GNL3L-induced cell proliferation, in contrast, the knockdown of LDOC1 potentiates cell proliferation upon GNL3L expression. Interestingly, GNL3L upregulates NF-κB dependent transcriptional activity by modulating the expression of NF-κB subunit p65, which is reversed upon co-expression of LDOC1 with GNL3L. GNL3L also potentiates TNF-α mediated NF-κB activity. In addition, anti-apoptotic function of GNL3L is impaired upon p65 knockdown, suggesting its critical role in GNL3L mediated cell proliferation/survival. An inverse correlation of GNL3L and LDOC1 expression profiles in various tumor tissues from BioXpress database indicate their critical role in cancer. Collectively, our data provides evidence that GNL3L-LDOC1 interplay regulates cell proliferation through the modulation of NF-κB pathway during tumorigenesis.

Published
2016

14. Guanine nucleotide binding protein like-1 (GNL1) promotes cancer cell proliferation and survival through AKT/p21 CIP1signaling cascade

Author

Krishnan, Rehna, Murugiah, Mariappan, Lakshmi, Naga Padma, and Mahalingam, Sundarasamy

Abstract

GNL1 inhibits cell apoptosis and promotes cell growth by inducing cytoplasmic retention and stabilization of p21 through AKT-mediated phosphorylation. Our data elucidate a novel GNL1/AKT/p21 signaling cascade to provide a growth benefit to cancer cells and this may be an ideal target for cancer therapeutic intervention.

Published
2020
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16. BRCA1 and Metastasis: Outcome of Defective DNA Repair.

Author

Krishnan, Rehna, Patel, Parasvi S., and Hakem, Razqallah

Subjects
*DNA, *GENETIC mutation, *GENETICS, *BRCA genes, *METASTASIS, *DNA damage
Abstract

Simple Summary: BRCA1 has critical functions in accurately repairing double stand breaks in the DNA through a process known as homologous recombination. BRCA1 also has various functions in other cellular processes that safeguard the genome. Thus, mutations or silencing of this tumor suppressor significantly increases the risk of developing breast, ovarian, and other cancers. Metastasis refers to the spread of cancer to other parts of the body and is the leading cause of cancer-related deaths. In this review, we discuss the mechanisms by which BRCA1 mutations contribute to the metastatic and aggressive nature of the tumor cells. Heritable mutations in BRCA1 and BRCA2 genes are a major risk factor for breast and ovarian cancer. Inherited mutations in BRCA1 increase the risk of developing breast cancers by up to 72% and ovarian cancers by up to 69%, when compared to individuals with wild-type BRCA1. BRCA1 and BRCA2 (BRCA1/2) are both important for homologous recombination-mediated DNA repair. The link between BRCA1/2 mutations and high susceptibility to breast cancer is well established. However, the potential impact of BRCA1 mutation on the individual cell populations within a tumor microenvironment, and its relation to increased aggressiveness of cancer is not well understood. The objective of this review is to provide significant insights into the mechanisms by which BRCA1 mutations contribute to the metastatic and aggressive nature of the tumor cells. [ABSTRACT FROM AUTHOR]

Published
2022
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17. Nucleolar Pol II interactome reveals TBPL1, PAF1, and Pol I at intergenic rDNA drive rRNA biogenesis.

Author

Khosraviani N, Yerlici VT, St-Germain J, Hou YY, Cao SB, Ghali C, Bokros M, Krishnan R, Hakem R, Lee S, Raught B, and Mekhail K

Subjects
Humans, RNA Polymerase II metabolism, RNA Polymerase II genetics, RNA, Untranslated metabolism, RNA, Untranslated genetics, DNA, Intergenic genetics, HeLa Cells, RNA Polymerase I metabolism, RNA Polymerase I genetics, RNA, Ribosomal metabolism, RNA, Ribosomal genetics, Cell Nucleolus metabolism, DNA, Ribosomal genetics, DNA, Ribosomal metabolism, Nuclear Proteins metabolism, Nuclear Proteins genetics, Transcription Factors metabolism, Transcription Factors genetics
Abstract

Ribosomal DNA (rDNA) repeats harbor ribosomal RNA (rRNA) genes and intergenic spacers (IGS). RNA polymerase (Pol) I transcribes rRNA genes yielding rRNA components of ribosomes. IGS-associated Pol II prevents Pol I from excessively synthesizing IGS non-coding RNAs (ncRNAs) that can disrupt nucleoli and rRNA production. Here, compartment-enriched proximity-dependent biotin identification (compBioID) revealed the TATA-less-promoter-binding TBPL1 and transcription-regulatory PAF1 with nucleolar Pol II. TBPL1 localizes to TCT motifs, driving Pol II and Pol I and maintaining its baseline ncRNA levels. PAF1 promotes Pol II elongation, preventing unscheduled R-loops that hyper-restrain IGS Pol I-associated ncRNAs. PAF1 or TBPL1 deficiency disrupts nucleolar organization and rRNA biogenesis. In PAF1-deficient cells, repressing unscheduled IGS R-loops rescues nucleolar organization and rRNA production. Depleting IGS Pol I-dependent ncRNAs is sufficient to compromise nucleoli. We present the nucleolar interactome of Pol II and show that its regulation by TBPL1 and PAF1 ensures IGS Pol I ncRNAs maintaining nucleolar structure and function., (© 2024. The Author(s).)

Published
2024
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