The Role of WRN Helicase/Exonuclease in DNA Replication

Humans possess five distinct RecQ helicases (see Figure 1), all of which possess a hallmark RecQ helicase domain. Mutation or loss in any one of three human RecQ helicases give rise to genetic instability syndromes: WRN mutation gives Werner’s syndrome (WS), BLM loss results in Bloom syndrome (BS), and Rothmund-Thomson syndrome (RTS) is caused by mu‐ tation of RECQL41. WRN has come to prominence because its loss of function results in hu‐ man Werner’s syndrome, a segmental progeria (premature ageing) characterised by many signs and symptoms of normal ageing at both the organismal and cellular levels, with short‐ ened lifespan (median age of death 47 years [2]). In particular WS patients suffer from osteo‐ porosis, athero-and arterio-sclerosis and a high cancer incidence (particularly sarcoma) together with metabolic disorders normally associated with increased age, especially type II diabetes and lipodystrophy. Furthermore, patients show outwardly recognisable signs of ageing such as cataracts, greying hair and skin wrinkling, while female WS patients suffer premature menopause and both sexes show hypogonadism, with decreased fertility (re‐ viewed in ref. [2]).