Human DNA2 possesses a cryptic DNA unwinding activity that functionally integrates with BLM or WRN helicases.
Human DNA2 (hDNA2) contains both a helicase and a nuclease domain within the same polypeptide. The nuclease of hDNA2 is involved in a variety of DNA metabolic processes. Little is known about the role of the hDNA2 helicase. Using bulk and single-molecule approaches, we show that hDNA2 is a processive helicase capable of unwinding kilobases of dsDNA in length. The nuclease activity prevents the engagement of the helicase by competing for the same substrate, hence prominent DNA unwinding by hDNA2 alone can only be observed using the nuclease-deficient variant. We show that the helicase of hDNA2 functionally integrates with BLM or WRN helicases to promote dsDNA degradation by forming a heterodimeric molecular machine. This collectively suggests that the hDNA2 motor promotes the enzyme's capacity to degrade dsDNA in conjunction with BLM or WRN and thus promote the repair of broken DNA.
Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
Cosimo
C
Pinto
Institute of Experimental Physics I, University of Leipzig, Leipzig, Germany.
Kristina
K
Kasaciunaite
Institute of Experimental Physics I, University of Leipzig, Leipzig, Germany.
Ralf
R
Seidel
Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
Petr
0000-0002-9087-032X
P
Cejka
D004247:DNA / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism*; D006801:Humans; D055503:Protein Multimerization; D053484:RecQ Helicases / Q000378:metabolism*; D000071657:Werner Syndrome Helicase / Q000378:metabolism*
D004247:DNA; C097151:Bloom syndrome protein; D004265:DNA Helicases; C509908:DNA2 protein, human; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase
DNA end resection; DNA helicase; biochemistry; chromosomes; genes; homologous recombination; human