Post-translational modifications of proliferating cell nuclear antigen: A key signal integrator for DNA damage response (Review)

Abstract

Previous studies have shown that the post-translational modifications of proliferating cell nuclear antigen (PCNA) may be crucial in influencing the cellular choice between different pathways, such as the cell cycle checkpoint, DNA repair or apoptosis pathways, in order to maintain genomic stability. DNA damage leads to replication stress and the subsequent induction of PCNA modification by small ubiquitin (Ub)-related modifiers and Ub, which has been identified to affect multiple biological processes of genomic DNA. Thus far, much has been learned concerning the behavior of modified PCNA as a key signal integrator in response to DNA damage. In humans and yeast, modified PCNA activates DNA damage bypass via an error-prone or error-free pathway to prevent the breakage of DNA replication forks, which may potentially induce double-strand breaks and subsequent chromosomal rearrangements. However, the exact mechanisms by which these pathways work and by what means the modified PCNA is involved in these processes remain elusive. Thus, the improved understanding of PCNA modification and its implications for DNA damage response may provide us with more insight into the mechanisms by which human cells regulate aberrant recombination events, and cancer initiation and development. The present review focuses on the post-translational modifications of PCNA and its important functions in mediating mammalian cellular response to different types of DNA damage.

Keywords: DNA damage response; post-translational modification; proliferating cell nuclear antigen; small ubiquitin-related modifier; ubiquitin.

Figure 1

Role of Ub and SUMO modification of PCNA. PCNA may be modified by monoubiquitination, Lys-63-linked polyUb chains or SUMO at the same lysine 164 residue. PCNA monoubiquitination catalyzed by Rad6 and Rad18 directly activates TLS polymerases (such as pol η, Rev1 and pol ζ), which enable error-free or error-prone damage bypass, whereas Ubc13/Mms2 and Rad5 are required to extend the modification by a Lys-63-linked polyUb chain. PCNA polyubiquitination may occur if TLS fails, which subsequently results in a recombination-related error-free DNA damage tolerance pathway. Sumoylation of PCNA occurs in the S phase and attracts the antirecombinogenic helicase, Srs2, to inhibit unwanted recombination during DNA synthesis, however, ubiquitination of PCNA specifically occurs in cells with DNA damage or stalled replication. SUMO, small ubiquitin-related modifier; PCNA, proliferating cell nuclear antigen; pol, polymerase; TLS, translesion synthesis; UBC, ubiquitin-conjugating; DSB, double-strand break; Ub, ubiquitin; HR, homologous recombination.