Werner syndrome protein (WRN) is a
RecQ helicase that participates in DNA repair,
genome stability and cellular senescence. The five human
RecQ helicases, RECQL1, Bloom, WRN, RECQL4 and RECQL5 play critical roles in DNA repair and cell survival
after treatment with the anticancer drug
camptothecin (
CPT).
CPT derivatives are widely used in
cancer chemotherapy to inhibit
topoisomerase I and generate
DNA double-strand breaks during replication. Here we studied the effects of
CPT on the stability and expression dynamics of human
RecQ helicases. In the cells treated with
CPT, we observed distinct effects on WRN compared to other human
RecQ helicases.
CPT altered the cellular localization of WRN and induced its degradation by a
ubiquitin-mediated
proteasome pathway. WRN knockdown cells as well as
CPT treated cells became senescent and stained positive for senescence-associated β-
galactosidase at a higher frequency compared to control cells. However, the senescent phenotype was attenuated by ectopic expression of WRN suggesting functional implication of WRN degradation in
CPT treated cells. Approximately 5-23% of
breast cancer tumors are known to respond to
CPT-based
chemotherapy. Interestingly, we found that the extent of
CPT-induced WRN degradation correlates with increasing sensitivity of
breast cancer cells to
CPT. The abundance of WRN decreased in
CPT-treated sensitive cells; however, WRN remained relatively stable in
CPT-resistant
breast cancer cells. In a large clinical cohort of
breast cancer patients, we find that WRN and
topoisomerase I expression correlate with an aggressive
tumor phenotype and poor prognosis. Our novel observations suggest that WRN abundance along with
CPT-induced degradation could be a promising strategy for personalizing
CPT-based
cancer chemotherapeutic regimens.