Base excision repair and double strand break repair cooperate to modulate the formation of unrepaired double strand breaks in mouse brain

Aris A. Polyzos (), Ana Cheong, Jung Hyun Yoo, Lana Blagec, Sneh M. Toprani, Zachary D. Nagel and Cynthia T. McMurray ()
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Aris A. Polyzos: Lawrence Berkeley National Laboratory
Ana Cheong: Harvard T.H. Chan School of Public Health
Jung Hyun Yoo: Lawrence Berkeley National Laboratory
Lana Blagec: Lawrence Berkeley National Laboratory
Sneh M. Toprani: Harvard T.H. Chan School of Public Health
Zachary D. Nagel: Harvard T.H. Chan School of Public Health
Cynthia T. McMurray: Lawrence Berkeley National Laboratory

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract We lack the fundamental information needed to understand how DNA damage in the brain is generated and how it is controlled over a lifetime in the absence of replication check points. To address these questions, here, we integrate cell-type and region-specific features of DNA repair activity in the normal brain. The brain has the same repair proteins as other tissues, but normal, canonical repair activity is unequal and is characterized by high base excision repair (BER) and low double strand break repair (DSBR). The natural imbalance creates conditions where single strand breaks (SSBs) can convert to double strand breaks (DSBs) and reversibly switch between states in response to oxidation both in vivo and in vitro. Our data suggest that, in a normal background of repair, SSBs and DSBs are in an equilibrium which is pushed or pulled by metabolic state. Interconversion of SSB to DSBs provides a physiological check point, which would allow the formation of unrepaired DSBs for productive functions, but would also restrict them from exceeding tolerable limits.

Date: 2024
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DOI: 10.1038/s41467-024-51906-5

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