TY - JOUR
T1 - HMCES safeguards replication from oxidative stress and ensures error-free repair
AU - Srivastava, Mrinal
AU - Su, Dan
AU - Zhang, Huimin
AU - Chen, Zhen
AU - Tang, Mengfan
AU - Nie, Litong
AU - Chen, Junjie
N1 - Funding Information:
We thank all the members of the Chen laboratory for their help and constructive discussions. This work was supported in part grants from the Cancer Prevention & Research Institute of Texas (RP160667) and the U.S. National Institutes of Health (CA157448, CA193124) to J.C. J.C. also received support from the Pamela and Wayne Garrison Distinguished Chair in Cancer Research. We thank MD Anderson's Flow Cytometry and Cellular Imaging Facility (supported by MD Anderson's NIH Cancer Center Support Grant, P30CA016672) for their help with the flow cytometry experiments. Dr. Mrinal Srivastava received support from an MD Anderson Odyssey postdoctoral fellowship.
Publisher Copyright:
© 2020 The Authors
PY - 2020/6/4
Y1 - 2020/6/4
N2 - Replication across oxidative DNA lesions can give rise to mutations that pose a threat to genome integrity. How such lesions, which escape base excision repair, get removed without error during replication remains unknown. Our PCNA-based screen to uncover changes in replisome composition under different replication stress conditions had revealed a previously unknown PCNA-interacting protein, HMCES/C3orf37. Here, we show that HMCES is a critical component of the replication stress response, mainly upon base misincorporation. We further demonstrate that the absence of HMCES imparts resistance to pemetrexed treatment due to error-prone bypass of oxidative damage. Furthermore, based on genetic screening, we show that homologous recombination repair proteins, such as CtIP, BRCA2, BRCA1, and PALB2, are indispensable for the survival of HMCES KO cells. Hence, HMCES, which is the sole member of the SRAP superfamily in higher eukaryotes known so far, acts as a proofreader on replication forks, facilitates resolution of oxidative base damage, and therefore ensures faithful DNA replication.
AB - Replication across oxidative DNA lesions can give rise to mutations that pose a threat to genome integrity. How such lesions, which escape base excision repair, get removed without error during replication remains unknown. Our PCNA-based screen to uncover changes in replisome composition under different replication stress conditions had revealed a previously unknown PCNA-interacting protein, HMCES/C3orf37. Here, we show that HMCES is a critical component of the replication stress response, mainly upon base misincorporation. We further demonstrate that the absence of HMCES imparts resistance to pemetrexed treatment due to error-prone bypass of oxidative damage. Furthermore, based on genetic screening, we show that homologous recombination repair proteins, such as CtIP, BRCA2, BRCA1, and PALB2, are indispensable for the survival of HMCES KO cells. Hence, HMCES, which is the sole member of the SRAP superfamily in higher eukaryotes known so far, acts as a proofreader on replication forks, facilitates resolution of oxidative base damage, and therefore ensures faithful DNA replication.
KW - antimetabolite inhibitors
KW - base excision repair
KW - oxidative damage
KW - replication stress
KW - translesion synthesis
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U2 - 10.15252/embr.201949123
DO - 10.15252/embr.201949123
M3 - Article
C2 - 32307824
AN - SCOPUS:85083638956
SN - 1469-221X
VL - 21
JO - EMBO reports
JF - EMBO reports
IS - 6
M1 - e49123
ER -