ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells
Priyanka Verma,Yeqiao Zhou,Zhendong Cao,Peter V. Deraska,Moniher Deb,Eri Arai,Weihua Li,Yue Shao,Laura N. Puentes,Yiwen Li,Sonali Patankar,Robert H. Mach,Robert B. Faryabi,Junwei Shi,Roger A. Greenberg +14 more
TLDR
Using a CRISPR-based screen, this article identified the PAR-binding chromatin remodeller ALC1/CHD1L as a key determinant of PARPi toxicity in HR-deficient cells.Abstract:
The response to poly(ADP-ribose) polymerase inhibitors (PARPi) is dictated by homologous recombination (HR) DNA repair and the abundance of lesions that trap PARP enzymes. It remains unclear, however, if the established role of PARP in promoting chromatin accessibility impacts viability in these settings. Using a CRISPR-based screen, we identified the PAR-binding chromatin remodeller ALC1/CHD1L as a key determinant of PARPi toxicity in HR-deficient cells. ALC1 loss reduced viability of breast cancer gene (BRCA)-mutant cells and enhanced sensitivity to PARPi by up to 250-fold, while overcoming several resistance mechanisms. ALC1 deficiency reduced chromatin accessibility concomitant with a decrease in the association of base damage repair factors. This resulted in an accumulation of replication-associated DNA damage, increased PARP trapping and a reliance on HR. These findings establish PAR-dependent chromatin remodelling as a mechanistically distinct aspect of PARPi responses and therapeutic target in HR-deficient cancers.read more
Citations
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Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency
Ke Cong,Min Peng,Arne Nedergaard Kousholt,Wei Ting C. Lee,Silviana Lee,Sumeet Nayak,John J. Krais,Pamela S. VanderVere-Carozza,Katherine S. Pawelczak,Jennifer A. Calvo,Nicholas J. Panzarino,John J. Turchi,Neil Johnson,Jos Jonkers,Eli Rothenberg,Sharon B. Cantor +15 more
TL;DR: In this paper, BRCA1-deficient cells have elevated poly(ADP-ribose) and chromatin-associated PARP1, but aberrantly low XRCC1 consistent with defects in backup Okazaki fragment processing (OFP).
Journal ArticleDOI
Targeting DNA damage response pathways in cancer
Journal ArticleDOI
The expanding universe of PARP1-mediated molecular and therapeutic mechanisms.
Dan Huang,W. Lee Kraus +1 more
TL;DR: In this paper , the authors summarize the expanding array of molecular mechanisms underlying the biological functions of nuclear PARPs with a focus on PARP1, the founding member of the family, including roles in DNA repair, chromatin regulation, gene expression, ribosome biogenesis, and RNA biology.
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Exploiting synthetic lethality to target BRCA1/2-deficient tumors: where we stand
TL;DR: In this paper, the authors present the most recent findings on the use of PARPi in the clinic, which are currently approved for second-line therapy for advanced ovarian and breast cancer associated with mutations of BRCA1/BRCA2 genes.
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Rapid Detection and Signaling of DNA Damage by PARP-1.
Nootan Pandey,Ben E. Black +1 more
TL;DR: In this article, the authors review the full cycle of detecting DNA damage by PARP-1, PARP activation upon DNA binding, and PARP release from a DNA break, and discuss the allosteric consequence upon binding of PARP inhibitors.
References
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TL;DR: Burrows-Wheeler Alignment tool (BWA) is implemented, a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps.
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TL;DR: It is proposed that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair and exploited in order to kill BRCA2-deficient tumours by PARP inhibition alone.
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Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors
Junko Murai,Shar Yin N. Huang,Benu Brata Das,Amelie Renaud,Yiping Zhang,James H. Doroshow,Jiuping Ji,Shunichi Takeda,Yves Pommier +8 more
TL;DR: This study shows that PARP inhibitors trap the PARP1 and PARP2 enzymes at damaged DNA, providing a new mechanistic foundation for the rational application ofPARP inhibitors in cancer therapy.
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53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks
Samuel F. Bunting,Elsa Callen,Nancy Wong,Hua Tang Chen,Federica Polato,Amanda Gunn,Anne Bothmer,Niklas Feldhahn,Oscar Fernandez-Capetillo,Liu Cao,Xiaoling Xu,Chu-Xia Deng,Toren Finkel,Michel C. Nussenzweig,Michel C. Nussenzweig,Jeremy M. Stark,André Nussenzweig +16 more
TL;DR: It is shown that DNA breaks in Brca1-deficient cells are aberrantly joined into complex chromosome rearrangements by a process dependent on the nonhomologous end-joining (NHEJ) factors 53BP1 and DNA ligase 4, illustrating that HR and NHEJ compete to process DNA breaks that arise during DNA replication.