Linking abnormal mitosis to the acquisition of DNA damage Neil

Correspondence to Neil J. Ganem: [email protected] Introduction Progression from a nontransformed normal cell to a malignant cancer cell requires multiple genetic changes that hyperactivate oncogenes while restraining tumor suppressors (Hanahan and Weinberg, 2011). This occurs via two distinct, but not mutually exclusive, mechanisms: the acquisition of genetic mutations, and gene copy number changes. Genetic mutations arise as a consequence of cells failing to efficiently detect, repair, and/or respond to DNA damage, and may be subtle (e.g., single nucleotide changes) or more complex (e.g., amplifications, deletions, insertions, translocations; Negrini et al., 2010). Mutations can arise spontaneously, as a consequence of endogenous genotoxic stress, such as from stalled/collapsing replication forks generated during S phase or reactive oxygen species produced by normal metabolic activity (Spry et al., 2007; Hoeijmakers, 2009; Branzei and Foiani, 2010; Ciccia and Elledge, 2010). However, environmental and/ or genetic perturbations that markedly increase DNA damage— and subsequent mutation rates—greatly facilitate oncogenesis. This is best illustrated by the significant predisposition to cancer in familial genetic diseases where components of DNA repair or checkpoint signaling are lost or mutated; examples include hereditary nonpolyposis colorectal cancer syndrome (HNPCC; mutations in MLH1, MSH2, MSH6, or PMS2; Spry et al., 2007; Hoeijmakers, 2009), hereditary breast and ovarian cancer syndrome (mutations in BRCA1 and BRCA2; Fackenthal and Olopade, 2007), Fanconi anemia (caused by mutations in any of a number of Fanconi genes important for DNA repair; Moldovan and D’Andrea, 2009), and Li-Fraumeni syndrome (mutations in TP53; Varley et al., 1997). Independent of DNA damage and mutation, whole chromosome and segmental aneuploidies can also dramatically alter gene copy number of relevant oncogenes and tumor suppressors. Recent mouse models demonstrate that merely elevating the rates of chromosome missegregation is sufficient to promote tumor development in vivo, at least in part by facilitating loss of heterozygosity of known tumor suppressor genes (Weaver et al., 2007; Baker et al., 2009; Baker and van Deursen, 2010). A number of cellular defects are known to generate whole chromosome aneuploidy, including atypical mitotic spindle assembly, inefficient chromosome congression, abnormal microtubule dynamics, cohesion and condensation defects, supernumerary centrosomes, and a defective spindle assembly checkpoint (Schvartzman et al., 2010; Compton, 2011; Gordon et al., 2012; Holland and Cleveland, 2012). The common factor among these defects is that they all manifest during mitosis, when chromosomes physically separate. Thus, it is widely accepted that abnormal mitosis can contribute to tumorigenesis via the generation of aneuploidy. One unresolved question concerns the extent to which abnormal mitosis and DNA damage, the two key promoters of genomic instability, are linked. Although it has been known for some time that DNA damage adversely affects the efficacy of mitosis, the reciprocal possibility—that abnormal mitosis promotes DNA damage—has been largely overlooked in studies of cancer cell biology. However, several recent reports demonstrate that abnormal mitosis alone is sufficient to generate DNA damage. Thus, impaired mitosis may negatively effect genome stability in two ways: not only by causing genome destabilizing whole chromosome aneuploidy, but also by promoting the acquisition of potentially growth-promoting mutations.