TY - JOUR
T1 - Orc6 is a component of the replication fork and enables efficient mismatch repair
AU - Lin, Yo Chuen
AU - Liu, Dazhen
AU - Chakraborty, Arindam
AU - Kadyrova, Lyudmila Y.
AU - Song, You Jin
AU - Hao, Qinyu
AU - Mitra, Jaba
AU - Hsu, Rosaline Y.C.
AU - Arif, Mariam K.
AU - Adusumilli, Sneha
AU - Liao, Ting Wei
AU - Ha, Taekjip
AU - Kadyrov, Farid A.
AU - Prasanth, Kannanganattu V.
AU - Prasanth, Supriya G.
N1 - ACKNOWLEDGMENTS. We thank members of the S.G.P. and K.V.P. laboratory for discussions and suggestions. We thank Drs. M. Aladjem, J. Cook, A. Dutta, M. Mechali, B. Moriarity, S. Nair, B. Stillman, M. Wold, and L. Zou for providing reagents and suggestions. We thank Dr. D. Rivier for critical reading of the manuscript. This work was supported by an NSF\u2013Cellular and Molecular Mechanics and BioNanotechnology\u2013Integrative Graduate Education and Research Traineeship fellowship to R.Y.C.H.; NIH (R35 GM 122569) and NSF (PHY 1430124) awards to T.H.; NIH award (R01GM132128) to F.A.K.; Cancer Center at Illinois seed grant and Prairie Dragon Paddlers and NSF Early-Concept Grants for Exploratory Research (grant MCB1723008) awards and NIH grant R01GM132458 and R21AG065748 to K.V.P.; and Cancer Center at Illinois seed grant, NSF (1243372 and 1818286) and NIH (R01GM125196) awards to S.G.P. T.H. is an investigator with Howard Hughes Medical Institute.
PY - 2022/5/31
Y1 - 2022/5/31
N2 - In eukaryotes, the origin recognition complex (ORC) is required for the initiation of DNA replication. The smallest subunit of ORC, Orc6, is essential for prereplication complex (pre-RC) assembly and cell viability in yeast and for cytokinesis in metazoans. However, unlike other ORC components, the role of human Orc6 in replication remains to be resolved. Here, we identify an unexpected role for hOrc6, which is to promote S-phase progression after pre-RC assembly and DNA damage response. Orc6 localizes at the replication fork and is an accessory factor of the mismatch repair (MMR) complex. In response to oxidative damage during S phase, often repaired by MMR, Orc6 facilitates MMR complex assembly and activity, without which the checkpoint signaling is abrogated. Mechanistically, Orc6 directly binds to MutSα and enhances the chromatin-association of MutLα, thus enabling efficient MMR. Based on this, we conclude that hOrc6 plays a fundamental role in genome surveillance during S phase.
AB - In eukaryotes, the origin recognition complex (ORC) is required for the initiation of DNA replication. The smallest subunit of ORC, Orc6, is essential for prereplication complex (pre-RC) assembly and cell viability in yeast and for cytokinesis in metazoans. However, unlike other ORC components, the role of human Orc6 in replication remains to be resolved. Here, we identify an unexpected role for hOrc6, which is to promote S-phase progression after pre-RC assembly and DNA damage response. Orc6 localizes at the replication fork and is an accessory factor of the mismatch repair (MMR) complex. In response to oxidative damage during S phase, often repaired by MMR, Orc6 facilitates MMR complex assembly and activity, without which the checkpoint signaling is abrogated. Mechanistically, Orc6 directly binds to MutSα and enhances the chromatin-association of MutLα, thus enabling efficient MMR. Based on this, we conclude that hOrc6 plays a fundamental role in genome surveillance during S phase.
KW - ATR
KW - DNA damage
KW - Orc6
KW - mismatch repair
KW - replication
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U2 - 10.1073/pnas.2121406119
DO - 10.1073/pnas.2121406119
M3 - Article
C2 - 35622890
AN - SCOPUS:85131108242
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 - 22
M1 - e2121406119
ER -