INO80 and γ-H2AX Interaction Links ATP-Dependent Chromatin Remodeling to DNA Damage Repair

4022 Background: The prognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. Polybromo-1 ( PBRM1) is a subunit of the PBF chromatin-remodeling complex and preclinical studies suggest induction of synthetic lethality by PARP inhibitors in PBRM1-mutated cancers. Therefore, we aimed to describe the molecular landscape in BTC harboring PBRM1 mutations. Methods: 1,848 BTC samples were included in this study. Specimens were analyzed using NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Pathway gene enrichment analyses were done using GSEA (Subramaniam 2015, PNAS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). Survival was calculated from time of tissue collection to last contact using Kaplan-Meier estimates. Results: PBRM1 mutations were identified in 8.1% (n = 150) of BTC tumors and were more prevalent in intrahepatic BTC (9.9%) than in gallbladder cancer (6%, p = 0.0141) and in extrahepatic BTC (4.5%, p = 0.008). In PBRM1-mutated tumors, we found a higher rate of MSI-H/dMMR (8.7% vs. 2.1%, p < 0.0001) and a higher median TMB (4 vs. 3 mt/MB, p < 0.0001). When compared to PBRM1-wildtype cancers higher rates of co-mutations in chromatin-remodeling genes (e.g. ARID1A, 31% vs. 16% , p < 0.0001) and DNA damage repair pathway (e.g. ATRX, 4.4% vs. 0.3%, p < 0.0001) were detected. Within PBRM1-mutated tumors, a significant higher frequency of infiltrating M1 macrophages was observed (p < 0.0001). Gene set enrichment analysis revealed that genes associated with tumor inflammation (e.g. HLA-DRA, HLA-DRB1, IFNGR1) were enriched in PBRM1-mutated tumors (NES = 2.02, FDR = 1.3%, p < 0.0001). Overall survival analysis showed that PBRM1 mutations were associated with a favorable outcome (HR 1.502, 95% CI [1.013-2.227], p = 0.041). This relationship was also present in MSS subgroup (HR: 1.667, [1.026-2.71], p = 0.037). Conclusions: This is the largest and most extensive molecular profiling study focusing on PBRM1-mutated BTC. Co-mutations in chromatin-remodelling and DNA damage repair genes might set the stage for clinical testing of PARP inhibitors in PBRM1-mutated BTC. Moreover, a distinct tumor microenvironment characterized by high M1 macrophages infiltration and an enrichment of inflammatory genes suggest a potential benefit of immunotherapy.

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Molecular basis of chromatin remodeling by Rhp26, a yeast CSB ortholog

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1818163116 ◽

2019 ◽

Vol 116 (13) ◽

pp. 6120-6129 ◽

Cited By ~ 2

Author(s):

Wei Wang ◽

Jun Xu ◽

Oliver Limbo ◽

Jia Fei ◽

George A. Kassavetis ◽

...

Keyword(s):

Gene Expression ◽

Dna Damage ◽

Molecular Mechanism ◽

Chromatin Remodeling ◽

Molecular Basis ◽

Dna Damage Repair ◽

Genome Integrity ◽

Chromatin Remodelers ◽

Free Dna ◽

Damage Repair

CSB/ERCC6 belongs to an orphan subfamily of SWI2/SNF2-related chromatin remodelers and plays crucial roles in gene expression, DNA damage repair, and the maintenance of genome integrity. The molecular basis of chromatin remodeling by Cockayne syndrome B protein (CSB) is not well understood. Here we investigate the molecular mechanism of chromatin remodeling by Rhp26, aSchizosaccharomyces pombeCSB ortholog. The molecular basis of chromatin remodeling and nucleosomal epitope recognition by Rhp26 is distinct from that of canonical chromatin remodelers, such as imitation switch protein (ISWI). We reveal that the remodeling activities are bidirectionally regulated by CSB-specific motifs: the N-terminal leucine-latch motif and the C-terminal coupling motif. Rhp26 remodeling activities depend mainly on H4 tails and to a lesser extent on H3 tails, but not on H2A and H2B tails. Rhp26 promotes the disruption of histone cores and the release of free DNA. Finally, we dissected the distinct contributions of two Rhp26 C-terminal regions to chromatin remodeling and DNA damage repair.

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Chromatin Remodeling, DNA Damage Repair and Aging

Current Genomics ◽

10.2174/138920212803251373 ◽

2012 ◽

Vol 13 (7) ◽

pp. 533-547 ◽

Cited By ~ 25

Author(s):

Baohua Liu ◽

Raymond K.H Yip ◽

Zhongjun Zhou

Keyword(s):

Dna Damage ◽

Chromatin Remodeling ◽

Dna Damage Repair ◽

Damage Repair

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Verticillium dahliae chromatin remodeling facilitates the DNA damage repair in response to plant ROS stress

PLoS Pathogens ◽

10.1371/journal.ppat.1008481 ◽

2020 ◽

Vol 16 (4) ◽

pp. e1008481 ◽

Cited By ~ 2

Author(s):

Sheng Wang ◽

Xue-Ming Wu ◽

Chuan-Hui Liu ◽

Jing-Yun Shang ◽

Feng Gao ◽

...

Keyword(s):

Dna Damage ◽

Chromatin Remodeling ◽

Verticillium Dahliae ◽

Dna Damage Repair ◽

Damage Repair

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Genomic alterations associated with mutational signatures, DNA damage repair and chromatin remodeling pathways in cervical carcinoma

npj Genomic Medicine ◽

10.1038/s41525-021-00244-2 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Mari K. Halle ◽

Aishwarya Sundaresan ◽

Jianqing Zhang ◽

Chandra Sekhar Pedamallu ◽

Vinodh Srinivasasainagendra ◽

...

Keyword(s):

Cervical Cancer ◽

Dna Damage ◽

Chromatin Remodeling ◽

Squamous Cell ◽

Dna Damage Repair ◽

Squamous Cell Carcinomas ◽

Large Sample Size ◽

Multiple Datasets ◽

Damage Repair ◽

Whole Exome

AbstractDespite recent advances in the prevention of cervical cancer, the disease remains a leading cause of cancer-related deaths in women worldwide. By applying the GISTIC2.0 and/or the MutSig2CV algorithms on 430 whole-exome-sequenced cervical carcinomas, we identified previously unreported significantly mutated genes (SMGs) (including MSN, GPX1, SPRED3, FAS, and KRT8), amplifications (including NFIA, GNL1, TGIF1, and WDR87) and deletions (including MIR562, PVRL1, and NTM). Subset analyses of 327 squamous cell carcinomas and 86 non-squamous cell carcinomas revealed previously unreported SMGs in BAP1 and IL28A, respectively. Distinctive copy number alterations related to tumors predominantly enriched for *CpG- and Tp*C mutations were observed. CD274, GRB2, KRAS, and EGFR were uniquely significantly amplified within the Tp*C-enriched tumors. A high frequency of aberrations within DNA damage repair and chromatin remodeling genes were detected. Facilitated by the large sample size derived from combining multiple datasets, this study reveals potential targets and prognostic markers for cervical cancer.

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