Interaction between the helicases genetically linked to Fanconi anemia group J and Bloom's syndrome

TY - JOUR

T1 - Interaction between the helicases genetically linked to Fanconi anemia group J and Bloom's syndrome

AU - Suhasini, Avvaru N

AU - Rawtani, Nina A

AU - Wu, Yuliang

AU - Sommers, Joshua A

AU - Sharma, Sudha

AU - Mosedale, Georgina

AU - North, Phillip S

AU - Cantor, Sharon B

AU - Hickson, Ian D

AU - Brosh, Robert M

PY - 2011/2/16

Y1 - 2011/2/16

N2 - Bloom's syndrome (BS) and Fanconi anemia (FA) are autosomal recessive disorders characterized by cancer and chromosomal instability. BS and FA group J arise from mutations in the BLM and FANCJ genes, respectively, which encode DNA helicases. In this work, FANCJ and BLM were found to interact physically and functionally in human cells and co-localize to nuclear foci in response to replication stress. The cellular level of BLM is strongly dependent upon FANCJ, and BLM is degraded by a proteasome-mediated pathway when FANCJ is depleted. FANCJ-deficient cells display increased sister chromatid exchange and sensitivity to replication stress. Expression of a FANCJ C-terminal fragment that interacts with BLM exerted a dominant negative effect on hydroxyurea resistance by interfering with the FANCJ-BLM interaction. FANCJ and BLM synergistically unwound a DNA duplex substrate with sugar phosphate backbone discontinuity, but not an 'undamaged' duplex. Collectively, the results suggest that FANCJ catalytic activity and its effect on BLM protein stability contribute to preservation of genomic stability and a normal response to replication stress.

AB - Bloom's syndrome (BS) and Fanconi anemia (FA) are autosomal recessive disorders characterized by cancer and chromosomal instability. BS and FA group J arise from mutations in the BLM and FANCJ genes, respectively, which encode DNA helicases. In this work, FANCJ and BLM were found to interact physically and functionally in human cells and co-localize to nuclear foci in response to replication stress. The cellular level of BLM is strongly dependent upon FANCJ, and BLM is degraded by a proteasome-mediated pathway when FANCJ is depleted. FANCJ-deficient cells display increased sister chromatid exchange and sensitivity to replication stress. Expression of a FANCJ C-terminal fragment that interacts with BLM exerted a dominant negative effect on hydroxyurea resistance by interfering with the FANCJ-BLM interaction. FANCJ and BLM synergistically unwound a DNA duplex substrate with sugar phosphate backbone discontinuity, but not an 'undamaged' duplex. Collectively, the results suggest that FANCJ catalytic activity and its effect on BLM protein stability contribute to preservation of genomic stability and a normal response to replication stress.

U2 - 10.1038/emboj.2010.362

DO - 10.1038/emboj.2010.362

M3 - Journal article

C2 - 21240188

SN - 0261-4189

VL - 30

SP - 692

EP - 705

JO - E M B O Journal

JF - E M B O Journal

IS - 4

ER -