Zheng, H.-X. | Search bioRxiv

bioRxiv2023

CHAF1A promotes the translesion DNA synthesis pathway in response to DNA replication stress

The translesion DNA synthesis (TLS) pathway mediated by proliferating cell nuclear antigen (PCNA) monoubiquitination is an essential mechanism by which cancer cells bypass DNA damage caused by DNA replication stress to maintain genomic stability and cell survival. Chromatin assembly factor 1 subunit A (CHAF1A) traditionally promotes histone assembly during DNA replication. Here, we revealed that CHAF1A is a novel regulator of the TLS pathway. High expression of CHAF1A is significantly associated with poor prognosis in cancer patients. CHAF1A promotes fork restart under DNA replication stress and maintains genome integrity. CHAF1A enhances the interaction between PCNA and E3 ubiquitin protein ligase RAD18 and promotes PCNA monoubiquitination, thereby promoting the recruitment of Y-family DNA polymerase Pol {eta} and enhancing cancer cell resistance to stimuli that trigger replication fork blockade. Mechanistically, CHAF1A-mediated PCNA monoubiquitination is independent of CHAF1A-PCNA interaction. CHAF1A interacts with both RAD18 and replication protein A2 (RPA2), mediating RAD18 binding on chromatin in response to DNA replication stress. Taken together, these findings improve our understanding of the mechanisms that regulate the TLS pathway and provide insights into the relationship between CHAF1A and the malignant progression of cancers.

cell biology↗

bioRxiv2019

Inland-coastal bifurcation of southern East Asians revealed by Hmong-Mien genomic history

The early history of the Hmong-Mien language family and its speakers is elusive. A good variety of Hmong-Mien-speaking groups distribute in Central China. Here, we report 903 high-resolution Y-chromosomal, 624 full-sequencing mitochondrial, and 415 autosomal samples from 20 populations in Central China, mainly Hunan Province. We identify an autosomal component which is commonly seen in all the Hmong-Mien-speaking populations, with nearly unmixed composition in Pahng. In contrast, Hmong and Mien respectively demonstrate additional genomic affinity to Tibeto-Burman and Kra-Dai speakers. We also discover two prevalent uniparental lineages of Hmong-Mien speakers. Y-chromosomal haplogroup O2a2a1b1a1b-N5 diverged [~]2,330 years before present (BP), approximately coinciding with the estimated time of Proto-Hmong-Mien ([~]2,500 BP), whereas mitochondrial haplogroup B5a1c1a significantly correlates with Pahng and Mien. All the evidence indicates a founding population substantially contributing to present-day Hmong-Mien speakers. Consistent with the two distinct routes of agricultural expansion from southern China, this Hmong-Mien founding ancestry is phylogenetically closer to the founding ancestry of Neolithic Mainland Southeast Asians and present-day isolated Austroasiatic-speaking populations than Austronesians. The spatial and temporal distribution of the southern East Asian lineage is also compatible with the scenario of out-of-southern-China farming dispersal. Thus, our finding reveals an inland-coastal genetic discrepancy related to the farming pioneers in southern China and supports an inland southern China origin of an ancestral meta-population contributing to both Hmong-Mien and Austroasiatic speakers.

genetics↗