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FAM111A regulates replication origin activation and cell fitness.

ABSTRACT: FAM111A is a replisome-associated protein and dominant mutations within its trypsin-like peptidase domain are linked to severe human developmental syndrome, the Kenny-Caffey syndrome. However, FAM111A functions remain unclear. Here, we show that FAM111A facilitates efficient activation of DNA replication origins. Upon hydroxyurea treatment, FAM111A-depleted cells exhibit reduced single-stranded DNA formation and a better survival rate. Unrestrained expression of FAM111A WT and patient mutants causes accumulation of DNA damage and cell death, only when the peptidase domain remains intact. Unrestrained expression of FAM111A WT also causes increased single-stranded DNA formation that relies on S phase entry, FAM111A peptidase activity but not its binding to proliferating cell nuclear antigen. Altogether, these data unveil how FAM111A promotes DNA replication under normal conditions and becomes harmful in a disease context.

SUBMITTER: Rios-Szwed DO

PROVIDER: S-EPMC10551639 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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FAM111A regulates replication origin activation and cell fitness.

Rios-Szwed Diana O DO Alvarez Vanesa V Sanchez-Pulido Luis L Garcia-Wilson Elisa E Jiang Hao H Bandau Susanne S Lamond Angus A Alabert Constance C

Life science alliance 20231004 12

FAM111A is a replisome-associated protein and dominant mutations within its trypsin-like peptidase domain are linked to severe human developmental syndrome, the Kenny-Caffey syndrome. However, FAM111A functions remain unclear. Here, we show that FAM111A facilitates efficient activation of DNA replication origins. Upon hydroxyurea treatment, FAM111A-depleted cells exhibit reduced single-stranded DNA formation and a better survival rate. Unrestrained expression of FAM111A WT and patient mutants ca ...[more]

PMID: 37793778

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FAM111A regulates replication origin activation and cell fitness

Project description:FAM111A is a replisome associated protein and dominant mutations within its trypsin-like peptidase domain are linked to severe human developmental syndrome, the Kenny-Caffey syndrome. However, FAM111A functions remain unclear. Here, we show that FAM111A facilitates efficient activation of DNA replication origins. Upon replication fork stalling, FAM111A promotes dormant origin activation and ssDNA exposure. Furthermore, unrestrained expression of FAM111A wild-type as well as patient mutants causes accumulation of DNA damage and cell death, only when the peptidase domain remains intact. The peptidase domain is responsible for ssDNA exposure during S phase, which is not caused by caspase dependent apoptosis. Altogether, these data unveil how FAM111A promotes DNA replication in normal conditions and becomes harmful in a disease context.

2023-10-03 | PXD044180 | Pride

BRPF3-HBO1 regulates replication origin activation and histone H3K14 acetylation.

Project description:During DNA replication, thousands of replication origins are activated across the genome. Chromatin architecture contributes to origin specification and usage, yet it remains unclear which chromatin features impact on DNA replication. Here, we perform a RNAi screen for chromatin regulators implicated in replication control by measuring RPA accumulation upon replication stress. We identify six factors required for normal rates of DNA replication and characterize a function of the bromodomain and PHD finger-containing protein 3 (BRPF3) in replication initiation. BRPF3 forms a complex with HBO1 that specifically acetylates histone H3K14, and genomewide analysis shows high enrichment of BRPF3, HBO1 and H3K14ac at ORC1-binding sites and replication origins found in the vicinity of TSSs. Consistent with this, BRPF3 is necessary for H3K14ac at selected origins and efficient origin activation. CDC45 recruitment, but not MCM2-7 loading, is impaired in BRPF3-depleted cells, identifying a BRPF3-dependent function of HBO1 in origin activation that is complementary to its role in licencing. We thus propose that BRPF3-HBO1 acetylation of histone H3K14 around TSS facilitates efficient activation of nearby replication origins.

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Project description:Safeguards against excess DNA replication are often dysregulated in cancer, and driving cancer cells towards over-replication is a promising therapeutic strategy. We determined DNA synthesis patterns in cancer cells undergoing partial genome re-replication due to perturbed regulatory interactions (re-replicating cells). These cells exhibited slow replication, increased frequency of replication initiation events, and a skewed initiation pattern that preferentially reactivated early-replicating origins. Unlike in cells exposed to replication stress, which activated a novel group of hitherto unutilized (dormant) replication origins, the preferred re-replicating origins arose from the same pool of potential origins as those activated during normal growth. Mechanistically, the skewed initiation pattern reflected a disproportionate distribution of pre-replication complexes on distinct regions of licensed chromatin prior to replication. This distinct pattern suggests that circumventing the strong inhibitory interactions that normally prevent excess DNA synthesis can occur via at least two pathways, each activating a distinct set of replication origins.

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The Hsk1(Cdc7) replication kinase regulates origin efficiency.

Project description:Origins of DNA replication are generally inefficient, with most firing in fewer than half of cell cycles. However, neither the mechanism nor the importance of the regulation of origin efficiency is clear. In fission yeast, origin firing is stochastic, leading us to hypothesize that origin inefficiency and stochasticity are the result of a diffusible, rate-limiting activator. We show that the Hsk1-Dfp1 replication kinase (the fission yeast Cdc7-Dbf4 homologue) plays such a role. Increasing or decreasing Hsk1-Dfp1 levels correspondingly increases or decreases origin efficiency. Furthermore, tethering Hsk1-Dfp1 near an origin increases the efficiency of that origin, suggesting that the effective local concentration of Hsk1-Dfp1 regulates origin firing. Using photobleaching, we show that Hsk1-Dfp1 is freely diffusible in the nucleus. These results support a model in which the accessibility of replication origins to Hsk1-Dfp1 regulates origin efficiency and provides a potential mechanistic link between chromatin structure and replication timing. By manipulating Hsk1-Dfp1 levels, we show that increasing or decreasing origin firing rates leads to an increase in genomic instability, demonstrating the biological importance of appropriate origin efficiency.

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Replication origin selection regulates the distribution of meiotic recombination.

Project description:The program of DNA replication, defined by the temporal and spatial pattern of origin activation, is altered during development and in cancers. However, whether changes in origin usage play a role in regulating specific biological processes remains unknown. We investigated the consequences of modifying origin selection on meiosis in fission yeast. Genome-wide changes in the replication program of premeiotic S phase do not affect meiotic progression, indicating that meiosis neither activates nor requires a particular origin pattern. In contrast, local changes in origin efficiencies between different replication programs lead to changes in Rad51 recombination factor binding and recombination frequencies in these domains. We observed similar results for Rad51 when changes in efficiencies were generated by directly targeting expression of the Cdc45 replication factor. We conclude that origin selection is a key determinant for organizing meiotic recombination, providing evidence that genome-wide modifications in replication program can modulate cellular physiology.

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FAM111A protects replication forks from protein obstacles via its trypsin-like domain.

Project description:Persistent protein obstacles on genomic DNA, such as DNA-protein crosslinks (DPCs) and tight nucleoprotein complexes, can block replication forks. DPCs can be removed by the proteolytic activities of the metalloprotease SPRTN or the proteasome in a replication-coupled manner; however, additional proteolytic mechanisms may exist to cope with the diversity of protein obstacles. Here, we show that FAM111A, a PCNA-interacting protein, plays an important role in mitigating the effect of protein obstacles on replication forks. This function of FAM111A requires an intact trypsin-like protease domain, the PCNA interaction, and the DNA-binding domain that is necessary for protease activity in vivo. FAM111A, but not SPRTN, protects replication forks from stalling at poly(ADP-ribose) polymerase 1 (PARP1)-DNA complexes trapped by PARP inhibitors, thereby promoting cell survival after drug treatment. Altogether, our findings reveal a role of FAM111A in overcoming protein obstacles to replication forks, shedding light on cellular responses to anti-cancer therapies.

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Developmental differences in genome replication program and origin activation.

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