The Multiple Roles of Ubiquitylation in Regulating Challenged DNA Replication

Abstract

DNA replication is essential for the propagation of life and the development of complex organisms. However, replication is a risky process as it can lead to mutations and chromosomal alterations. Conditions challenging DNA synthesis by replicative polymerases or DNA helix unwinding, generally termed as replication stress, can halt replication fork progression. Stalled replication forks are unstable, and mechanisms exist to protect their integrity, which promote an efficient restart of DNA synthesis and counteract fork collapse characterized by the accumulation of DNA lesions and mutagenic events. DNA replication is a highly regulated process, and several mechanisms control replication timing and integrity both during unperturbed cell cycles and in response to replication stress. Work over the last two decades has revealed that key steps of DNA replication are controlled by conjugation of the small peptide ubiquitin. While ubiquitylation was traditionally linked to protein degradation, the complexity and flexibility of the ubiquitin system in regulating protein function have recently emerged. Here we review the multiple roles exerted by ubiquitin-conjugating enzymes and ubiquitin-specific proteases, as well as readers of ubiquitin chains, in the control of eukaryotic DNA replication and replication-coupled DNA damage tolerance and repair.

Activating the Anaphase Promoting Complex to Enhance Genomic Stability and Prolong Lifespan

“…Furthermore, entire loss of CDH1 increased DNA damage accumulation, driving progression of murine and human B-cell acute leukemia [ 138 ]. It was also revealed that many cancer cell lines lack the ability to activate APC Cdh1 when under replication stress [ 139 , 140 ], and that CDH1-depleted cells undergo senescence in G2, suggesting that APC Cdh1 may normally act as a barrier to genome instability [ 123 ]. Support for this idea comes from studies using SIRT2, an antitumor and lifespan-extending protein, which activates the APC by deacetylating CDC20 and CDH1; SIRT2-deficient mice exhibited higher levels of cancer and elevated levels of APC substrates [ 83 ].…”

Working on Genomic Stability: From the S-Phase to Mitosis

“…Some TLS polymerases, such as Pol eta and Pol kappa, play a role in replicating CFSs independent of PCNA (Proliferating Cell Nuclear Antigen) ubiquitylation in both cancerous and normal mammalian cell lines [153][154][155]. However, the ability of evolutionary conserved key TLS enzymes to synthesize DNA in eukaryotes is enhanced by PCNA mono-ubiquitylation [156][157][158][159][160], as reviewed in [161]. The role of ubiquitin and SUMO modifications in DNA replication has been reviewed [162].…”