Abstract
DNA replication is a tightly regulated conserved process that ensures the faithful transmission of genetic material to define heritable phenotypic traits. Perturbations in this process result in genomic instability, mutagenesis, and diseases, including malignancy. Proteins involved in the initiation, progression, and termination of DNA replication are subject to a plethora of reversible post-translational modifications (PTMs) to provide a proper temporal and spatial control of replication. Among these, modifications involving the covalent attachment of the small protein ubiquitin or the small ubiquitin-like modifier (SUMO) to replication and replication-associated proteins are particularly important for the proper regulation of DNA replication as well as for optimal cellular responses to replication stress. In this article, we describe how the ubiquitination and SUMOylation processes impact DNA replication in eukaryotes and highlight the consequences of deregulated signals emanating from these two versatile regulatory pathways on cellular activities.
Highlights
Eukaryotic DNA replication is tightly regulated such that cells replicate their entire genome once and only once in a given cell cycle (Machida et al, 2005)
The six-subunit origin recognition complex (ORC) complex from high eukaryotes binds DNA without sequences specificity (Vashee et al, 2003; Schaarschmidt et al, 2004), replication initiates from genomic loci that are enriched for AT-rich sequences, dinucleotide repeats, asymmetrical purine-pyrimidine sequences, and matrix attachment region (MAR) sequences (Li and Stillman, 2012; Kumar and Remus, 2016)
In S. cerevisiae, the heterodimeric E2 ubiquitin conjugating enzyme, Ubc13-Mms2, which is recruited to chromatin by the RING-finger protein Rad5, can convert the mono-ubiquitinated Lys on proliferating cell nuclear antigen (PCNA) to Lys-63-linked polyubiquitin chain to participate in gap-filling damage tolerance (Prakash, 1981; Hoege et al, 2002; Torres-Ramos et al, 2002; Branzei et al, 2004; Haracska et al, 2004) and in template switching, an error-free pathway of DNA that utilizes the newly replicated sister chromatid as a template for replication (Hoege et al, 2002; Branzei et al, 2008, 2011; Choi et al, 2010; Hedglin and Benkovic, 2015)
Summary
Eukaryotic DNA replication is tightly regulated such that cells replicate their entire genome once and only once in a given cell cycle (Machida et al, 2005). The six-subunit ORC complex from high eukaryotes binds DNA without sequences specificity (Vashee et al, 2003; Schaarschmidt et al, 2004), replication initiates from genomic loci that are enriched for AT-rich sequences, dinucleotide repeats, asymmetrical purine-pyrimidine sequences, and matrix attachment region (MAR) sequences (Li and Stillman, 2012; Kumar and Remus, 2016) Additional epigenomic features, such as the DNA topology, transcription factors and regulatory elements, local chromatin environment as well as the replication initiation proteins CDT1 and CDC6 play a role for the selectivity of ORC to stably bind replication origins (Masai et al, 2010; Li and Stillman, 2012; Kumar and Remus, 2016). The conversion of H4K20me to H4K20me2/3 by SUV4-20H1/H2 likely plays an important role for SET8-dependent replication initiation, as the recruitment of ORC1 as well as the ORC-associated protein (ORCA) protein (both capable of binding H4K20me in vitro) to chromatin requires SUV4–20H1/H2 (Beck et al, 2012a)
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