Unfolding tyrosine kinase inhibitor sensitivity in chronic myeloid leukemia

Dna2 was first characterized in yeast as an essential gene encoding a protein with both helicase and endonuclease activities involved in maturation of Okazaki fragments during DNA replication. Dna2 also plays a role in double-strand break (DSB) repair by homolo-gous recombination. The respective contributions of its replication and/or repair functions toward cell viability and resistance to geno-toxic stress is not entirely clear. Recent studies, including that of Karanja et al. 1 in a recent issue of Cell Cycle, are starting to clarify the multifac-eted roles of DNA2. Together with the endonuclease Rad27 (Fen1 in higher eukaryotes), Dna2 removes 5' flaps generated by strand displacement during synthesis by Pol δ on the lagging strand. Most 5' flap processing during replication is due to the activity of Rad27, yet Rad27∆ yeast cells are viable, whereas Dna2∆ cells are not. This suggests that the essential role of Dna2 in genome maintenance is distinct from Okazaki fragment maturation. 2 indeed, Dna2 is a target of the intra-S-phase checkpoint in fission yeast and stabilizes replication forks. 3 Dna2 phos-phorylation by Cds1 promotes the association of Dna2 to replication forks to counteract fork reversal. Reversed forks can be erroneously recognized as recombination intermedi-ates leading genomic rearrangements. 4 Thus, Dna2 maintains genome stability by processing stalled forks before they collapse into aberrant structures. Similarly, Exo1 nuclease also participates in preventing the generation of " chicken-foot " structures from blocked forks, but, interestingly, Exo1 appears to be functional, even in the absence of an active checkpoint. 4 Homology-dependent repair requires the generation of 3' ssDNA, a process called resec-tion that is regulated by CDKs. Resection provides the template that is used by Rad51 recombinase to search for homologous sequences.5 Resection is initiated by the MRN (Mre11-Rad50-Nbs1) complex and its co-factor CtiP. More processive, long-range resection is then performed by two partially overlapping pathways involving Dna2 and/or Exo1. 5 in the November 2012 issue of Cell Cycle, Karanja et al. 1 provide additional evidence for the role of Dna2 and Exo1 in S-phase. Using siRNA-mediated Dna2 and Exo1 knock-down, they show that both nucleases contribute to cell viability following CPT, cisplatin or MMS treatments in a redundant manner. The data further support the conserved roles of Dna2 and Exo1 in the DNA damage response. Notably, the authors observe that Dna2-depleted cells have more profound defects in resection and Chk1 activation than Exo1-depleted cells when treated with cisplatin, a DNA-damaging …