@article{0fb5b19627ef48ceb30cd83560a11085,
title = "Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD",
abstract = "Chromatin is a barrier to efficient DNA repair, as it hinders access and processing of certain DNA lesions. ALC1/CHD1L is a nucleosome-remodeling enzyme that responds to DNA damage, but its precise function in DNA repair remains unknown. Here we report that loss of ALC1 confers sensitivity to PARP inhibitors, methyl-methanesulfonate, and uracil misincorporation, which reflects the need to remodel nucleosomes following base excision by DNA glycosylases but prior to handover to APEX1. Using CRISPR screens, we establish that ALC1 loss is synthetic lethal with homologous recombination deficiency (HRD), which we attribute to chromosome instability caused by unrepaired DNA gaps at replication forks. In the absence of ALC1 or APEX1, incomplete processing of BER intermediates results in post-replicative DNA gaps and a critical dependence on HR for repair. Hence, targeting ALC1 alone or as a PARP inhibitor sensitizer could be employed to augment existing therapeutic strategies for HRD cancers.",
keywords = "ALC1, base excsion repair, BRCAs, chromatin remodeler, DNA damage repair, DNA gycosylases, homologous recombination defieciency, PARPs, poly(ADP)-ribosylation, synthetic lethality",
author = "Graeme Hewitt and Valerie Borel and Sandra Segura-Bayona and Tohru Takaki and Phil Ruis and Roberto Bellelli and Lehmann, {Laura C.} and Lucia Sommerova and Aleksandra Vancevska and Antonia Tomas-Loba and Kang Zhu and Christopher Cooper and Kasper Fugger and Harshil Patel and Robert Goldstone and Deborah Schneider-Luftman and Ellie Herbert and Gordon Stamp and Rachel Brough and Stephen Pettitt and Lord, {Christopher J.} and West, {Stephen C.} and Ivan Ahel and Dragana Ahel and Chapman, {J. Ross} and Sebastian Deindl and Boulton, {Simon J.}",
note = "Funding Information: We thank members of the Boulton lab for suggestions, discussions, and critical reading of the manuscript and Anton Sabantsev for help with the design of nucleosome constructs. We thank the Crick BRF, GEMMs, and EHP for support with animal experiments. Work in I.A.?s group is funded by the Wellcome Trust (grant number 210634), BBSRC (BB/R007195/1), and Cancer Research UK (C35050/A22284). Work in D.A.?s group is funded by the Cancer Research UK Career Development Fellowship (grant number 16304). Work in the S.J.B. lab is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC0010048), the UK Medical Research Council (FC0010048), and the Wellcome Trust (FC0010048); a European Research Council (ERC) Advanced Investigator Grant (TelMetab); and Wellcome Trust Senior Investigator and Collaborative Grants. S.S.-B. was the recipient of an EMBO Long Term Fellowship (ALTF 707-2019) and a MSCA individual fellowship (grant 886577). Work in the J.R.C. group is funded by CRUK Career Development Fellowship (C52690/A19270) with infrastructural support from Wellcome core award 090532/Z/09/Z. G.H. and S.J.B. conceived the study; A.T.-L. and V.B. generated ALC1 knockout mice; V.B. conducted all animal experiments; G.H. S.S.-B. T.T. L.C.L. S.D. P.R. R. Bellelli. J.R.C. L.S. A.V. K.Z. C.C. D.A. I.A. and S.J.B. designed and conducted experiments; R.G. and H.P. generated and analyzed sequencing data for CRISPR screening. E.H. and G.S. performed histopathology. D.S.-L. performed TCGA survival analysis K.F. and S.C.W. provided insightful comments and shared reagents. G.H. and S.J.B. wrote the manuscript with help from S.S.-B. V.B. and R.B. and editorial input from all other authors. G.H. and S.J.B are inventors on a patent derived from this work. S.J.B. is also scientific co-founder and VP Science Strategy at Artios Pharma Ltd. Babraham Research Campus, Cambridge, UK. The authors declare no other competing interests. Funding Information: We thank members of the Boulton lab for suggestions, discussions, and critical reading of the manuscript and Anton Sabantsev for help with the design of nucleosome constructs. We thank the Crick BRF, GEMMs, and EHP for support with animal experiments. Work in I.A.{\textquoteright}s group is funded by the Wellcome Trust (grant number 210634 ), BBSRC ( BB/R007195/1 ), and Cancer Research UK ( C35050 / A22284 ). Work in D.A.{\textquoteright}s group is funded by the Cancer Research UK Career Development Fellowship (grant number 16304 ). Work in the S.J.B. lab is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK ( FC0010048 ), the UK Medical Research Council ( FC0010048 ), and the Wellcome Trust ( FC0010048 ); a European Research Council ( ERC ) Advanced Investigator Grant ( TelMetab ); and Wellcome Trust Senior Investigator and Collaborative Grants. S.S.-B. was the recipient of an EMBO Long Term Fellowship ( ALTF 707-2019 ) and a MSCA individual fellowship (grant 886577 ). Work in the J.R.C. group is funded by CRUK Career Development Fellowship ( C52690 /A19270) with infrastructural support from Wellcome core award 090532/Z/09/Z . Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2021",
month = feb,
day = "18",
doi = "10.1016/j.molcel.2020.12.006",
language = "English",
volume = "81",
pages = "767--783.e11",
journal = "MOLECULAR CELL",
issn = "1097-2765",
publisher = "Cell Press",
number = "4",
}
