TY - JOUR
T1 - The mismatch recognition protein MutSα promotes nascent strand degradation at stalled replication forks
AU - Zhang, Junqiu
AU - Zhao, Xin
AU - Liu, Lu
AU - Li, Hao Dong
AU - Gu, Liya
AU - Castrillon, Diego H.
AU - Li, Guo Min
N1 - Publisher Copyright:
Copyright © 2022 the Author(s). Published by PNAS.
PY - 2022/10/4
Y1 - 2022/10/4
N2 - Mismatch repair (MMR) is a replication-coupled DNA repair mechanism and plays multiple roles at the replication fork. The well-established MMR functions include correcting misincorporated nucleotides that have escaped the proofreading activity of DNA polymerases, recognizing nonmismatched DNA adducts, and triggering a DNA damage response. In an attempt to determine whether MMR regulates replication progression in cells expressing an ultramutable DNA polymerase E (PolE), carrying a proline-to-arginine substitution at amino acid 286 (PolE-P286R), we identified an unusual MMR function in response to hydroxyurea (HU)-induced replication stress. PolE-P286R cells treated with hydroxyurea exhibit increased MRE11-catalyzed nascent strand degradation. This degradation by MRE11 depends on the mismatch recognition protein MutSα and its binding to stalled replication forks. Increased MutSα binding at replication forks is also associated with decreased loading of replication fork protection factors FANCD2 and BRCA1, suggesting blockage of these fork protection factors from loading to replication forks by MutSα. We find that the MutSα-dependent MRE11-catalyzed fork degradation induces DNA breaks and various chromosome abnormalities. Therefore, unlike the well-known MMR functions of ensuring replication fidelity, the newly identified MMR activity of promoting genome instability may also play a role in cancer avoidance by eliminating rogue cells.
AB - Mismatch repair (MMR) is a replication-coupled DNA repair mechanism and plays multiple roles at the replication fork. The well-established MMR functions include correcting misincorporated nucleotides that have escaped the proofreading activity of DNA polymerases, recognizing nonmismatched DNA adducts, and triggering a DNA damage response. In an attempt to determine whether MMR regulates replication progression in cells expressing an ultramutable DNA polymerase E (PolE), carrying a proline-to-arginine substitution at amino acid 286 (PolE-P286R), we identified an unusual MMR function in response to hydroxyurea (HU)-induced replication stress. PolE-P286R cells treated with hydroxyurea exhibit increased MRE11-catalyzed nascent strand degradation. This degradation by MRE11 depends on the mismatch recognition protein MutSα and its binding to stalled replication forks. Increased MutSα binding at replication forks is also associated with decreased loading of replication fork protection factors FANCD2 and BRCA1, suggesting blockage of these fork protection factors from loading to replication forks by MutSα. We find that the MutSα-dependent MRE11-catalyzed fork degradation induces DNA breaks and various chromosome abnormalities. Therefore, unlike the well-known MMR functions of ensuring replication fidelity, the newly identified MMR activity of promoting genome instability may also play a role in cancer avoidance by eliminating rogue cells.
KW - MutSα
KW - chromosome instability
KW - nascent strand degradation
KW - replication fork stability
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U2 - 10.1073/pnas.2201738119
DO - 10.1073/pnas.2201738119
M3 - Article
C2 - 36161943
AN - SCOPUS:85138603218
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 40
M1 - e2201738119
ER -