Helicase/endonuclease WRN

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Helicase/endonuclease WRN

Gene WRN encodes a protein of 1,432 amino acids containing the seven signature motifs of the RecQ subfamily of DNA helicases that unwind nucleic acids in a 3'-to-5' direction in an ATP-dependent manner. RecQ helicases have been implicated in regulating genome stability, however, the specific mechanisms and pathways in which the WRN protein functions remain to be elucidated. WRN has been shown to interact with proteins involved in DNA repair, replication, and telomere maintenance. WRN-deficient cells exhibit chromosomal translocations and deletions (ibid.) and these cells are hypersensitive to DNA crosslinkers (cis-platinum, mitomycin-C, or 8-methoxypsoralen + UV light), and to camptothecin.

WRN protein has been shown to interact directly with human replication protein A (hRPA) which facilitates the DNA-unwinding activity of WRN, and to interact with Ku70 and Ku80 that are known to be involved in repairing DNA double strand breaks through the non-homologous end joining pathway. Although Ku proteins have no effect on the ATPase or helicase activity of WRN, they strongly stimulate specific exonuclease activity of WRN. WRN stimulates DNA synthesis by DNA polymerase d, an essential eukaryotic polymerase with central roles in DNA replication and DNA repair.

Involvement of WRN in replication may extend beyond telomeres. WS patient-derived primary fibroblasts were reported to replicate slowly and have a prolonged S phase, and a more recent study suggested an elevated rate of spontaneous replication fork inactivation in these cells. In response to camptothecin or hydroxyurea, WRN can colocalize with sites of DNA synthesis as marked by foci of BrdU incorporation or of the single stranded DNA binding protein, RPA. WRN can also colocalize with homologous recombination factor RAD51 and RAD51 paralogs, and with the ATR kinase. WRN is phosphorylated by ATR, the key regulator of the response to disrupted replication fork progression, and/or a related ATM kinase, which responds to DNA breaks.

Werner syndrome (WS) is an autosomal recessive human genetic instability disorder with features of cancer predisposition and premature aging. It is caused by mutations in a member of a conserved family of the RecQ helicase genes, WRN (RECQL2). Mutations in two other members of this protein family in humans also cause genetic instability and cancer predisposition syndromes. Loss of BLM results in Bloom syndrome, and mutations in RECQL4 lead to Rothmund-Thomson syndrome with a risk of osteosarcoma.