Regulation of Unperturbed DNA Replication by Ubiquitylation

Abstract

Posttranslational modification of proteins by means of attachment of a small globular protein ubiquitin (i.e., ubiquitylation) represents one of the most abundant and versatile mechanisms of protein regulation employed by eukaryotic cells. Ubiquitylation influences almost every cellular process and its key role in coordination of the DNA damage response is well established. In this review we focus, however, on the ways ubiquitylation controls the process of unperturbed DNA replication. We summarise the accumulated knowledge showing the leading role of ubiquitin driven protein degradation in setting up conditions favourable for replication origin licensing and S-phase entry. Importantly, we also present the emerging major role of ubiquitylation in coordination of the active DNA replication process: preventing re-replication, regulating the progression of DNA replication forks, chromatin re-establishment and disassembly of the replisome at the termination of replication forks.

Too Much of a Good Thing: How Ectopic DNA Replication Affects Bacterial Replication Dynamics

“…This does not mean that the fusion of forks is unproblematic in eukaryotic cells. On the contrary, recent work has highlighted that replisome disassembly is highly choreographed and that multiple accessory proteins, such as the helicases Rrm3 and Pif1, are necessary for bringing replication to an accurate conclusion (Steinacher et al, 2012;Maric et al, 2014;Moreno et al, 2014;Dewar et al, 2015;Moreno and Gambus, 2015;Dewar and Walter, 2017;Gambus, 2017;Deegan et al, 2019), highlighting that we have only just started to understand the mechanisms and regulation of fork fusion events both in bacteria and eukaryotes.…”

The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma

“…Following transition through the spindle assembly checkpoint, APC/C CDC20 promotes the degradation of securin and cyclin B, allowing chromatid segregation and mitotic exit. In late mitosis and G1, APC/C CDH1 participates in promoting licensing of DNA for replication by allowing the recruitment of the prereplicative complex to replication origins (Hernández-Carralero et al, 2018;Moreno and Gambus, 2015). This involves APC/C CDH1 -mediated degradation of geminin, which is an inhibitor of the key replication licensing factor CDT1, and suppression of cyclin A and B CDK complexes, which inhibit replication licensing.…”

“…RBX1/DDB1 depletion may elicit prosurvival responses through attenuation of CRLs in addition to CRL4 CDT2 . Similar to EMI1, CRL4 CDT2 is involved in protecting against DNA rereplication (Abbas and Dutta, 2011;Abbas and Dutta, 2017;Moreno and Gambus, 2015). During S-phase and DNA repair, CRL4 CDT2 promotes the DNA replicationecoupled proteasomal degradation of PCNAebound proteins involved in promoting replication licensing including CDT1, SET8, and p21 (Havens and Walter, 2011;Hernández-Carralero et al, 2018;Scrima et al, 2011).…”

Strategic role of the ubiquitin-dependent segregase p97 (VCP or Cdc48) in DNA replication

“…However, in the last decade, other posttranslational modifications, such as ubiquitination and SUMOylation, have emerged as being equally as important, but their role and function in the regulation of DNA replication are poorly understood (Bergink and Jentsch 2009;Moreno and Gambus 2015;Ulrich 2014). The molecular segregase p97 also known as valsoin-containing protein (VCP) in metazoan or Cdc48 in lower eukaryotes is a central molecule in the regulation of ubiquitinated substrates and thus plays an essential role in protein homeostasis.…”

“…In 2007, it was discovered that p97/CDC-48 binds and extracts polyubiquitinated protein kinase Aurora B from chromatin during mitosis (Ramadan et al 2007). Since this discovery, chromatin-associated protein removal and degradation (CAD) has been emerging as an essential process in the maintenance of genome stability (Beli and Jackson 2015;Dantuma et al 2014;Dantuma and Hoppe 2012;Moreno and Gambus 2015;Ramadan 2012). It seems that p97 plays a central role in CAD, and therefore, it has been recognised as a genome caretaker (Vaz et al 2013) (Fig.…”