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Introduction Ku70, encoded by XRCC6, is well known as forming a heterodimer with Ku80 participating in repairing DNA double-strand breaks (DSBs) by nonhomologous end joining (NHEJ) (1). Many studies have [...], Ku70, a DNA repair protein, binds to the damaged DNA ends and orchestrates the recruitment of other proteins to facilitate repair of DNA double-strand breaks. Besides its essential role in DNA repair, several studies have highlighted nonclassical functions of Ku70 in cellular processes. However, its function in immune homeostasis and antitumor immunity remains unknown. Here, we discovered a marked association between elevated Ku70 expression and unfavorable prognosis in lung adenocarcinoma, focusing specifically on increased Ku70 levels in tumor- infiltrated Tregs. Using a lung-colonizing tumor model in mice with Treg-specific Ku70 deficiency, we demonstrated that deletion of Ku70 in Tregs led to a stronger antitumor response and slower tumor growth due to impaired immune-suppressive capacity of Tregs. Furthermore, we confirmed that Ku70 played a critical role in sustaining the suppressive function of human Tregs. We found that Ku70 bound to forkhead box protein P3 (FOXP3) and occupied FOXP3-bound genomic sites to support its transcriptional activities. These findings not only unveil a nonhomologous end joining-independent (NHEJ-independent) role of Ku70 crucial for Treg-suppressive function, but also underscore the potential of targeting Ku70 as an effective strategy in cancer therapy, aiming to both restrain cancer cells and enhance pulmonary antitumor immunity.

1. Introduction As the aging population rapidly grows worldwide, by 2030, approximately one-fifth of the world's population will be aged 65 or more, and the prevalence of cardiovascular diseases will [...], RAD54B belongs to the SNF2/SWI2 superfamily, participating in homologous recombination repair. DNA damage is the central driver of aging, but there is no direct evidence of an association between RAD54B and vascular aging. The present study sought to investigate the role and mechanisms of RAD54B in endothelial senescence. In senescent animal models, including spontaneously hypertensive rats, normal aging mice, and D-gal- induced senescent mice, and senescent cell models induced by [H.sub.2][O.sub.2], D-gal, and culture, RAD54B was remarkably downregulated. Knockdown of RAD54B increased the expression of p53 and p21, increased the ratio of SA-[beta]-gal- positive cells, and decreased the proportion of EdU-positive cells. Conversely, overexpression of RAD54B reversed the senescent phenotypes stimulated by [H.sub.2][O.sub.2] and delayed replicative endothelial senescence. Mechanistically, silencing RAD54B compensatorily increased the expression of RAD51/XRCC4, which remained unchanged in [H.sub.2][O.sub.2]-induced senescence. RAD54B lacking the SNF2 domain could still reverse the increasing expression of p53/p21 induced by [H.sub.2][O.sub.2]. RAD54B reduced [gamma]H2A.X expression and inhibited the expression and phosphorylation of CHK1. In conclusion, RAD54B exerts a direct protective effect against DNA damage through enhancing homologous recombination repair in endothelial senescence, resulting in inhibition of the downstream CHK1/p53/p21 pathway, suggesting that RAD54B may be a potential therapeutic target for vascular aging-associated diseases. Key words: RAD54B, DNA damage repair, vascular endothelial senescence

MLH1 to the rescue Breast cancer 1 (BRCA1) and BRCA2 loss of heterozygosity (LOH) is a paradigmatic event in cancer initiation. However, the relationship between BRCA1/2 genetics and cellular fitness [...], While breast cancer 2 (BRCA2) loss of heterozygosity (LOH) promotes cancer initiation, it can also induce death in nontransformed cells. In contrast, mismatch repair gene mutL homolog 1 (MLH1) is a tumor-suppressor gene that protects cells from cancer development through repairing mismatched base pairs during DNA mismatch repair (MMR). Sengodan et al., in this issue of the JCI, reveal an interplay between the 2 genes: MLH1 promoted the survival of BRCA2-deficient cells independently of its MMR function. MLH1 protected replication forks from degradation, while also resolving R-loops, thereby reducing genomic instability. Moreover, MLH1 expression was regulated directly by estrogen, shedding light into the hormone-responsive nature of many BRCA2 mutant breast cancers. These results provide important insight into the genetics that drive the initiation of BRCA2-mutated breast cancers.

Introduction Gastric cancer (GC) is one of the commonly diagnosed and the leading causes of death in China in 2015 (Chen et al. 2016). Risk factors for GC comprise Helicobacter [...], The homology-dependent repair (HDR) pathway is involved in deoxyribonucleic acid (DNA) damage response (DDR), which is crucial to cancer cell survival after treatment with DNA damage agents, including cisplatin (CDDP). Here, we explored the interactions between exonuclease 1 (EXO1), a core gene in the HDR pathway, and CDDP resistance in gastric cancer (GC). Using bioinformatics analysis, we identified the HDR pathway as the most amplified pathway in DDR in GC. In addition, EXO1 was the core gene in the HDR pathway and showed the most significant amplification in GC. The amplification of EXO1 resulted in higher EXO1 expression in cancerous tissues, with malignant prognostic effects. Moreover, we upregulated or downregulated EXO1 in GC cells to examine its effects on the cell malignant phenotype and CDDP resistance in vitro and in vivo. The depletion of EXO1 inhibited cell proliferatory, migratory, and invasive activities, and provided apoptosis resistance to GC cells. EXO1 expression was elevated in CDDP-resistant cells. Ectopic expression of EXO1 increased the resistance of GC cells to CDDP, while downregulation of EXO1 increased the sensitivity of GC cells. Taken together, our study indicates that the HDR pathway is an important player in CDDP resistance in GC through the regulation of EXO1. Key words: DNA damage response, EXO1, gastric cancer, cisplatin resistance, homology-dependent repair pathway La voie de reparation par homologie (RH) joue un role dans la reaction aux dommages a l'ADN (RDA), cruciale a la survie des cellules cancereuses apres l'administration d'agents endommageant l'ADN, y compris le cisplatine (CDDP). Dans les presents travaux, nous avons explore les interactions entre EXO1, un gene central dans la voie de RH, de meme que la resistance au CDDP dans le cancer gastrique (CG). A l'aide d'analyses bioinformatiques, nous avons etabli que la voie de RH est la voie de signalisation la plus amplifiee dans la RDA dans le cas du CG. De plus, nous avons observe qu'EXO1 etait le gene central dans la voie de RH, avec l'amplification la plus importante dans le CG. L'amplification d'EXO1 entrainait une augmentation plus importante de l'expression d'EXO1 dans le tissu cancereux, avec des effets sur le pronostic de malignite. En outre, nous avons procede a une regulation a la hausse ou a la baisse d'EXO1 dans les cellules de CG en vue d'examiner ses effets sur le phenotype de malignite cellulaire et la resistance au CDDP in vitro et in vivo. La depletion d'EXO1 entrainait une inhibition des activites de proliferation, de migration et d'invasion des cellules de CG, avec une resistance a l'apoptose. L'expression d'EXO1 augmentait dans les cellules resistantes au CDDP. L'expression ectopique d'EXO1 entrainait une augmentation de la resistance des cellules de CG au CDDP, tandis que la regulation a la baisse d'EXO1 entrainait une augmentation de la sensibilite des cellules de CG. Dans l'ensemble, notre etude montre que la voie de RH joue un role important dans la resistance au CDDP dans le CG par l'intermediaire de la regulation d'EXO1. [Traduit par la Redaction] Mots-cles : reaction aux dommages a l'ADN, EXO1, cancer gastrique, resistance au cisplatine, voie de reparation par homologie

Author(s): Goran Kokic [sup.1] , Felix R. Wagner [sup.1] , Aleksandar Chernev [sup.2] , Henning Urlaub [sup.2] [sup.3] , Patrick Cramer [sup.1] Author Affiliations: (1) Department of Molecular Biology, Max [...], Transcription-coupled DNA repair removes bulky DNA lesions from the genome.sup.1,2 and protects cells against ultraviolet (UV) irradiation.sup.3. Transcription-coupled DNA repair begins when RNA polymerase II (Pol II) stalls at a DNA lesion and recruits the Cockayne syndrome protein CSB, the E3 ubiquitin ligase, CRL4.sup.CSA and UV-stimulated scaffold protein A (UVSSA).sup.3. Here we provide five high-resolution structures of Pol II transcription complexes containing human transcription-coupled DNA repair factors and the elongation factors PAF1 complex (PAF) and SPT6. Together with biochemical and published.sup.3,4 data, the structures provide a model for transcription-repair coupling. Stalling of Pol II at a DNA lesion triggers replacement of the elongation factor DSIF by CSB, which binds to PAF and moves upstream DNA to SPT6. The resulting elongation complex, EC.sup.TCR, uses the CSA-stimulated translocase activity of CSB to pull on upstream DNA and push Pol II forward. If the lesion cannot be bypassed, CRL4.sup.CSA spans over the Pol II clamp and ubiquitylates the RPB1 residue K1268, enabling recruitment of TFIIH to UVSSA and DNA repair. Conformational changes in CRL4.sup.CSA lead to ubiquitylation of CSB and to release of transcription-coupled DNA repair factors before transcription may continue over repaired DNA. The authors resolve the structure of five complexes containing RNA polymerase II and the CSA and CSB proteins, offering insight into how the repair of DNA lesions is coupled to transcription.