Abstract
The human DNA2 (DNA replication helicase/nuclease 2) protein is expressed in both the nucleus and mitochondria, where it displays ATPase-dependent nuclease and helicase activities. DNA2 plays an important role in the removing of long flaps in DNA replication and long-patch base excision repair (LP-BER), interacting with the replication protein A (RPA) and the flap endonuclease 1 (FEN1). DNA2 can promote the restart of arrested replication fork along with Werner syndrome ATP-dependent helicase (WRN) and Bloom syndrome protein (BLM). In mitochondria, DNA2 can facilitate primer removal during strand-displacement replication. DNA2 is involved in DNA double strand (DSB) repair, in which it is complexed with BLM, RPA and MRN for DNA strand resection required for homologous recombination repair. DNA2 can be a major protein involved in the repair of complex DNA damage containing a DSB and a 5′ adduct resulting from a chemical group bound to DNA 5′ ends, created by ionizing radiation and several anticancer drugs, including etoposide, mitoxantrone and some anthracyclines. The role of DNA2 in telomere end maintenance and cell cycle regulation suggests its more general role in keeping genomic stability, which is impaired in cancer. Therefore DNA2 can be an attractive target in cancer therapy. This is supported by enhanced expression of DNA2 in many cancer cell lines with oncogene activation and premalignant cells. Therefore, DNA2 can be considered as a potential marker, useful in cancer therapy. DNA2, along with PARP1 inhibition, may be considered as a potential target for inducing synthetic lethality, a concept of killing tumor cells by targeting two essential genes.
Highlights
The DNA2 (DNA replication helicase/nuclease 2) protein was firstly identified in the yeast Saccharomyces cerevisiae in the early eighties and was recognized to play an important role in DNA replication both in the nucleus and mitochondria due to its helicase and nuclease activities [1,2]
In DDR it plays an important role in DNA repair, mainly in homologous recombination repair, dealing with double-strand breaks
HHR and non-homologous end joining (NHEJ) are the main pathways of DSBs processing in human cells, but the regulation of the choice between them is still poorly known, despite it is a fundamental problem as these two DNA repair systems can produce substantially different DNA molecules
Summary
Duxin et al were the fifirst to demonstrate that human DNA2 is present both in the nucleus and mitochondria and similar to yeast, it is an essential protein for the stability of the nuclear genome, as its absence led to chroommoossoommaall aabbeerrrraattiioonnss [[88]]. The action of the fork can be reversed, which can be seen as a general pathway of replication reactivation, but its mechanism is not fully known [22] This process is initiated by replication fork regression, where the newly synthesized DNA on the leading and lagging strands anneal to form a Holliday junction, termed as ‘chicken-foot’ structure that is stabilized by annealing helicases such as SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) [23,24,25]. The effect of RECQ1 helicase is not the only mechanism restarting reversed replication fork and it was shown that DNA2 could contribute to this process even in RECQ1-deficient cells [33] This protein used its nuclease activity to degrade reversed fork and restarted replication in cooperation with ATPase activity of the Werner syndrome ATP-dependent helicase (WRN) (Figure 3). DNA2 is not the only other DNA helicase as PIF1, suppressor of var1 3-like (SUV3) and RecQ-like helicase 4 (RECQ4) can be found in an active state in mitochondria [32]
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