Orc6 is a component of the replication fork and enables efficient mismatch repair

作者：Yo-Chuen Lin, Dazhen Liu, Arindam Chakraborty, Lyudmila Y. Kadyrova, You Jin Song, Qinyu Hao, Jaba Mitra, Rosaline Y.C. Hsu, Mariam K. Arif, Sneha Adusumilli, Ting‐Wei Liao, Taekjip Ha, Farid A. Kadyrov, Kannanganattu V. Prasanth, Supriya G. Prasanth · 发表于：Proceedings of the National Academy of Sciences · 年份：2022 · DOI：10.1073/pnas.2121406119 · 被引用次数：25 · 研究领域：DNA Repair Mechanisms、Genetic factors in colorectal cancer、Genomics and Chromatin Dynamics

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.