DNA2—An Important Player in DNA Damage Response or Just Another DNA Maintenance Protein?

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.

Genome-wide CRISPR synthetic lethality screen identifies a role for the ADP-ribosyltransferase PARP14 in replication fork stability controlled by ATR

“…Multiple components of the pathway were identified, including the upstream components TOPBP1, MRE11, RPA3 and RAD9A, and the downstream kinase CHK1. Although not a direct component of the ATR pathway, the DNA2 nuclease-helicase, another top hit we validated, has been found to participate in ATR activation under certain conditions, at least in yeast (36,47).…”

“…For screen validation, as a proof of concept we first picked two of the functionally relevant top candidates, namely CHK1 and DNA2. Both CHK1 and DNA2 are key players in DNA damage repair and represent potential therapeutic targets for cancer therapy (35)(36)(37). To validate these candidates, we used both the original 8988T PARP14 KO6 cell line in which the screen was performed, as well as two additional PARP14-knockout 8988T clones, namely PARP14 KO14 and PARP14 KO19 (Figure 2A).…”

High-content Imaging-based Pooled CRISPR Screens in Mammalian Cells

“…Six genes are involved in spindle function and chromosome segregation, which includes KIF11 26 , NUP62 27 , SPDL1 28 and three core chromosomal passenger complex (CPC) components INCENP, AURKB and CDCA8 29,30 . Three genes function in DNA damage and repair, namely TICRR 31,32 , TOP2A 33,34 and RAD51 35,36 , while the remaining four play roles in histone synthesis (CASP8AP2 37 ), DNA maintenance (DNA2 38,39 ) and cell cycle regulation (SKA1 40,41 and FBXO5 22,23 ) (Supplementary file 3). Some of these functions might directly explain the larger nuclei phenotype after knock down.…”

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…276 Oncogene activation increases DNA replication stress, which can make at least a fraction of tumor cells highly dependent on DNA maintenance. 277 In addition to impairing DNA maintenance, DNA-PK inhibitors could affect immune responses at several levels, and therefore the kinetics and dynamics of adding them to a combination treatment scheme need to be studied. 276,278 The main difference between CQ and salinomycin is the capacity of salinomycin to both induce, and under some conditions inhibit the autophagic flux.…”