Sirtuin inhibition is synthetic lethal with BRCA1 or BRCA2 deficiency.
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Authors
Bajrami, I
Walker, C
Krastev, DB
Weekes, D
Song, F
Wicks, AJ
Alexander, J
Haider, S
Brough, R
Pettitt, SJ
Tutt, ANJ
Lord, CJ
Walker, C
Krastev, DB
Weekes, D
Song, F
Wicks, AJ
Alexander, J
Haider, S
Brough, R
Pettitt, SJ
Tutt, ANJ
Lord, CJ
Document Type
Journal Article
Date
2021-11-08
Date Accepted
2021-10-06
Abstract
PARP enzymes utilise NAD+ as a co-substrate for their enzymatic activity. Inhibition of PARP1 is synthetic lethal with defects in either BRCA1 or BRCA2. In order to assess whether other genes implicated in NAD+ metabolism were synthetic lethal with BRCA1 or BRCA2 gene defects, we carried out a genetic screen, which identified a synthetic lethality between BRCA1 and genetic inhibition of either of two sirtuin (SIRT) enzymes, SIRT1 or SIRT6. This synthetic lethal interaction was replicated using small-molecule SIRT inhibitors and was associated with replication stress and increased cellular PARylation, in contrast to the decreased PARylation associated with BRCA-gene/PARP inhibitor synthetic lethality. SIRT/BRCA1 synthetic lethality was reversed by genetic ablation of either PARP1 or the histone PARylation factor-coding gene HPF1, implicating PARP1/HPF1-mediated serine ADP-ribosylation as part of the mechanistic basis of this synthetic lethal effect. These observations suggest that PARP1/HPF1-mediated serine ADP-ribosylation, when driven by SIRT inhibition, can inadvertently inhibit the growth of BRCA-gene mutant cells.
Citation
Commun Biol, 2021, 4 (1), pp. 1270 - ?
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Source Title
Publisher
NATURE PORTFOLIO
ISSN
eISSN
2399-3642
Collections
Research Team
Gene Function