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Defective ALC1 nucl...
Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD
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Hewitt, Graeme (author)
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Borel, Valerie (author)
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Segura-Bayona, Sandra (author)
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Takaki, Tohru (author)
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Ruis, Phil (author)
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Bellelli, Roberto (author)
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- Lehmann, Laura C. (author)
- Uppsala universitet,Molekylär systembiologi,Science for Life Laboratory, SciLifeLab
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Sommerova, Lucia (author)
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Vancevska, Aleksandra (author)
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Tomas-Loba, Antonia (author)
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Zhu, Kang (author)
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Cooper, Christopher (author)
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Fugger, Kasper (author)
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Patel, Harshil (author)
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Goldstone, Robert (author)
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Schneider-Luftman, Deborah (author)
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Herbert, Ellie (author)
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Stamp, Gordon (author)
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Brough, Rachel (author)
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Pettitt, Stephen (author)
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Lord, Christopher J. (author)
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West, Stephen C. (author)
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Ahel, Ivan (author)
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Ahel, Dragana (author)
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Chapman, J. Ross (author)
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- Deindl, Sebastian (author)
- Uppsala universitet,Molekylär systembiologi,Science for Life Laboratory, SciLifeLab
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Boulton, Simon J. (author)
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(creator_code:org_t)
- Cell Press, 2021
- 2021
- English.
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In: Molecular Cell. - : Cell Press. - 1097-2765 .- 1097-4164. ; 81:4, s. 767-783.e11
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https://uu.diva-port... (primary) (Raw object)
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Cellbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Cell Biology (hsv//eng)
Keyword
- ALC1
- BRCAs
- DNA damage repair
- DNA gycosylases
- PARPs
- base excsion repair
- chromatin remodeler
- homologous recombination defieciency
- poly(ADP)-ribosylation
- synthetic lethality
Publication and Content Type
- ref (subject category)
- art (subject category)
Find in a library
To the university's database
- By the author/editor
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Hewitt, Graeme
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Borel, Valerie
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Segura-Bayona, S ...
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Takaki, Tohru
-
Ruis, Phil
-
Bellelli, Robert ...
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show more...
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Lehmann, Laura C ...
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Sommerova, Lucia
-
Vancevska, Aleks ...
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Tomas-Loba, Anto ...
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Zhu, Kang
-
Cooper, Christop ...
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Fugger, Kasper
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Patel, Harshil
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Goldstone, Rober ...
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Schneider-Luftma ...
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Herbert, Ellie
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Stamp, Gordon
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Brough, Rachel
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Pettitt, Stephen
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Lord, Christophe ...
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West, Stephen C.
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Ahel, Ivan
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Ahel, Dragana
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Chapman, J. Ross
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Deindl, Sebastia ...
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Boulton, Simon J ...
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Cell Biology
- Articles in the publication
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Molecular Cell
- By the university
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Uppsala University