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Instability of Human Mitochondrial DNA, Nuclear Genes and Diseases
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
In 2013 a new enzyme PRIMPOL was described and precharacterized as a protein exhibiting two activities – primase and polymerase with unusual properties: it can by itself start DNA synthesis and is extremely resistant to DNA damage18. PRIMPOL acts both in the nucleus and mitochondrion and seems to play similar role in both compartments – it rescues stalled replication forks by adding dNTP at the site of lesion19. It does not play a role in the initiation of replication. Only one variant in PRIMPOL (4q35.1) (p.Tyr89Asp) was suggested to play role in autosomal dominant high myopia20. Although it was proven that this variant negatively influences processivity of the enzyme21 it is difficult to say whether the proposed phenotype results from alteration of nuclear, mitochondrial or both functions. Moreover, the involvement of PRIMPOL mutation in high myopia was later questioned22. The RNA polymerase involved in transcription, playing the role of primase in mtDNA replication will be presented later.
Targeting translesion synthesis (TLS) to expose replication gaps, a unique cancer vulnerability
Published in Expert Opinion on Therapeutic Targets, 2021
Sumeet Nayak, Jennifer A. Calvo, Sharon B. Cantor
Conventionally, RS deriving from DNA lesions are thought to be countered by lesion tolerance mechanisms such as translesion synthesis (TLS). Lower-fidelity TLS polymerases facilitate polymerization across from a DNA lesion in cases where the high-fidelity DNA replicative polymerases stall and cannot replicate past the lesion [31]. One critical point of regulation that engages TLS is the mono-ubiquitination of lysine 164 (K164) of proliferating cell nuclear antigen (PCNA) that is mediated by the RAD18/RAD6 ubiquitin ligases, which initiates the switch from replicative to TLS polymerases. This ubiquitination serves as a platform to recruit TLS polymerases (POL η, POL ι, POL κ, REV1, POL ζ [also known as REV3/REV7], POL θ, and POL ν) that mediate lesion bypass either in the course of DNA replication or in a process of post-replication gap filling [32–38]. By interacting with one or more TLS polymerases, PCNA functions as a ‘tool belt’ to coordinate TLS polymerases in a concerted response that initiates with a TLS polymerase such as POL η or POL κ that inserts a nucleotide at the site of the lesion [39–43]. Extension past the lesion is mediated by a distinct TLS polymerase such as POL ζ followed by a final switch to the replicative polymerases [44,45]. Alternatively, TLS can be engaged independently of PCNA ubiquitination (PCNA Ub) via a REV1 scaffold domain ‘bridge’ that interacts with several TLS polymerases [46,47]. PRIMPOL, a DNA primase and TLS polymerase, can also operate independently of PCNA to restart stalled forks or re-prime replication ahead of a lesion [48–50]. These well-orchestrated TLS polymerase switching events and their regulating mechanisms are reviewed at length in the following articles [51–54].