RAD18 opposes transcription-associated genome instability through FANCD2 recruitment

Wells, James P.; Chang, Eun-Ha; Dinatto, Leticia; White, Justin; Ryall, Stephanie; Stirling, Peter C.

doi:10.1371/journal.pgen.1010309

Cited by 10 publications

(13 citation statements)

References 58 publications

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“…Figure 4A). In agreement with previous findings (Wells et al 2022), we found that RAD18 plays a role in FANCD2 recruitment upon MRS (Suppl. Figure 4B).…”

Section: Resultssupporting

confidence: 94%

“…These effects are partially dependent on the failure to recruit the Fanconi anaemia protein FANCD2 to R-loop-prone genomic sites (Wells et al 2022). Notably, in our context, FANCD2 localizes with R-loops after MRS, and this localization is more pronounced in cells lacking WRNIP1 and its UBZ domain.…”

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

“…The UBZ domain of WRNIP1 is implicated in the physical association with RAD18 (Kanu et al 2016). RAD18-deficient cells exhibit high levels of TRCs and accumulate DNA/RNA hybrids, leading to DNA double strand breaks and replication stress (Wells et al 2022). These effects are partially dependent on the failure to recruit the Fanconi anaemia protein FANCD2 to R-loop-prone genomic sites (Wells et al 2022).…”

Section: Discussionmentioning

confidence: 99%

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WRNIP1 prevents transcription-associated genomic instability

Valenzisi

Marabitti

Pichierri

et al. 2023

Preprint

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R-loops are non-canonical DNA structures that form during transcription and play diverse roles in various physiological processes. Disruption of R-loop homeostasis can lead to genomic instability and replication impairment, contributing to several human diseases, including cancer. Although the molecular mechanisms that protect cells against such events are not fully understood, recent research has identified the fork protection factors and the DNA damage response proteins as regulators of R-loop dynamics. Here, we identify the Werner helicase-interacting protein 1 (WRNIP1) as a novel factor that counteracts transcription-associated DNA damage upon replication perturbation. Loss of WRNIP1 leads to R-loop accumulation, resulting in collisions between the replisome and transcription machinery. We observe co-localization of WRNIP1 with transcription/replication complexes and R-loops after replication perturbation, suggesting its involvement in resolving transcription-replication conflicts. Moreover, WRNIP1-deficient cells show impaired replication restart from transcription-induced fork stalling. Notably, transcription inhibition and RNase H1 overexpression rescue all the defects caused by loss of WRNIP1. Importantly, our findings highlight the critical role of WRNIP1 ubiquitin-binding zinc finger (UBZ) domain in preventing pathological persistence of R-loops and limiting DNA damage, thereby safeguarding genome integrity.

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“…Figure 4A). In agreement with previous findings (Wells et al 2022), we found that RAD18 plays a role in FANCD2 recruitment upon MRS (Suppl. Figure 4B).…”

Section: Resultssupporting

confidence: 94%

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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WRNIP1 prevents transcription-associated genomic instability

Valenzisi

Marabitti

Pichierri

et al. 2023

Preprint

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“…We next investigated whether the PCNA ΔSL47 mutant affects genomic integrity in cells using various assays. Recent studies have shown that PCNA unloading, PCNA ubiquitination, and FEN1 are associated with DNA-RNA hybrids and R-loop regulation [39][40][41][42]. Since PCNA ΔSL47 showed a PCNA ubiquitination defect (Figs 3C, 3D and 4B-4D), similar to RAD18-deficient cells [40], we next assessed whether the PCNA ΔSL47 mutant affects cellular DNA-RNA hybrid levels.…”

Section: Pcna Ser46 and Leu47 Amino Acids Are Important For Genomic S...mentioning

confidence: 99%

PCNA Ser46-Leu47 residues are crucial in preserving genomic integrity

Kim

et al. 2023

PLoS ONE

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Proliferating cell nuclear antigen (PCNA) is a maestro of DNA replication. PCNA forms a homotrimer and interacts with various proteins, such as DNA polymerases, DNA ligase I (LIG1), and flap endonuclease 1 (FEN1) for faithful DNA replication. Here, we identify the crucial role of Ser46-Leu47 residues of PCNA in maintaining genomic integrity using in vitro, and cell-based assays and structural prediction. The predicted PCNAΔSL47 structure shows the potential distortion of the central loop and reduced hydrophobicity. PCNAΔSL47 shows a defective interaction with PCNAWT leading to defects in homo-trimerization in vitro. PCNAΔSL47 is defective in the FEN1 and LIG1 interaction. PCNA ubiquitination and DNA-RNA hybrid processing are defective in PCNAΔSL47-expressing cells. Accordingly, PCNAΔSL47-expressing cells exhibit an increased number of single-stranded DNA gaps and higher levels of γH2AX, and sensitivity to DNA-damaging agents, highlighting the importance of PCNA Ser46-Leu47 residues in maintaining genomic integrity.

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