UV-triggered P21 Degradation Facilitates Damaged-DNA Replication and Preserves Genomic Stability

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2013 Jun 1

PMID 23723248

Citations 33

Authors

Sabrina F Mansilla

Gaston Soria

Maria Belen Vallerga

Martin Habif

Wilner Martinez-Lopez

Carol Prives

Vanesa Gottifredi

Affiliations

Soon will be listed here.

Abstract

Although many genotoxic treatments upregulate the cyclin kinase inhibitor p21, agents such as UV irradiation trigger p21 degradation. This suggests that p21 blocks a process relevant for the cellular response to UV. Here, we show that forced p21 stabilization after UV strongly impairs damaged-DNA replication, which is associated with permanent deficiencies in the recruitment of DNA polymerases from the Y family involved in translesion DNA synthesis), with the accumulation of DNA damage markers and increased genomic instability. Remarkably, such noxious effects disappear when disrupting the proliferating cell nuclear antigen (PCNA) interacting motif of stable p21, thus suggesting that the release of PCNA from p21 interaction is sufficient to allow the recruitment to PCNA of partners (such as Y polymerases) relevant for the UV response. Expression of degradable p21 only transiently delays early replication events and Y polymerase recruitment after UV irradiation. These temporary defects disappear in a manner that correlates with p21 degradation with no detectable consequences on later replication events or genomic stability. Together, our findings suggest that the biological role of UV-triggered p21 degradation is to prevent replication defects by facilitating the tolerance of UV-induced DNA lesions.

Citing Articles

Human CST complex restricts excessive PrimPol repriming upon UV induced replication stress by suppressing p21.

Sang P, Jaiswal R, Lyu X, Chai W Nucleic Acids Res. 2024; 52(7):3778-3793.

PMID: 38348929 PMC: 11040158. DOI: 10.1093/nar/gkae078.

The levels of p53 govern the hierarchy of DNA damage tolerance pathway usage.

Castano B, Schorer S, Guo Y, Calzetta N, Gottifredi V, Wiesmuller L Nucleic Acids Res. 2024; 52(7):3740-3760.

PMID: 38321962 PMC: 11039994. DOI: 10.1093/nar/gkae061.

Correction: Chromosomal Integrity after UV Irradiation Requires FANCD2-Mediated Repair of Double Strand Breaks.

Federico M, Vallerga M, Radl A, Paviolo N, Bocco J, Di Giorgio M PLoS Genet. 2023; 19(12):e1011094.

PMID: 38117757 PMC: 10732383. DOI: 10.1371/journal.pgen.1011094.

Polymerase iota (Pol ι) prevents PrimPol-mediated nascent DNA synthesis and chromosome instability.

Mansilla S, Bertolin A, Venerus Arbilla S, Castano B, Jahjah T, Singh J Sci Adv. 2023; 9(15):eade7997.

PMID: 37058556 PMC: 10104471. DOI: 10.1126/sciadv.ade7997.

Revisiting the Function of p21 in DNA Repair: The Influence of Protein Interactions and Stability.

Ticli G, Cazzalini O, Stivala L, Prosperi E Int J Mol Sci. 2022; 23(13).

PMID: 35806061 PMC: 9267019. DOI: 10.3390/ijms23137058.

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