Merotelic attachments and non-homologous end joining are the basis of chromosomal instability

Abstract

Although the large majority of solid tumors show a combination of mitotic spindle defects and chromosomal instability, little is known about the mechanisms that govern the initial steps in tumorigenesis. The recent report of spindle-induced DNA damage provides evidence for a single mechanism responsible for the most prominent genetic defects in chromosomal instability. Spindle-induced DNA damage is brought about by uncorrected merotelic attachments, which cause kinetochore distortion, chromosome breakage at the centromere, and possible activation of DNA damage repair pathways. Although merotelic attachments are common early in mitosis, some escape detection by the kinetochore pathway. As a consequence, a proportion of merotelic attachments gives rise to chromosome breakage in normal cells and in carcinomas. An intrinsic chromosome segregation defect might thus form the basis of tumor initiation. We propose a hypothesis in which merotelic attachments and chromosome breakage establish a feedback loop that results in relaxation of the spindle checkpoint and suppression of anti-proliferative pathways, thereby promoting carcinogenesis.

The Human Cleavage Stage Embryo Is a Cradle of Chromosomal Rearrangements

“…Interestingly, both BFB cycles and chromosomal arm imbalances are typical features of chromosome instability in tumors [Bignell et al, 2007;Guerrero et al, 2010b]. Furthermore, by developing novel algorithms that interpret SNP array-based profiles of single-cell genomes, we recently detected also the formation of segmental uniparental disomies (UPDs) in human cleavage stage embryogenesis [unpubl.…”

“…2 ). These unstable chromosome fragments may further develop into telocentric chromosomes, arm ring chromosomes, i(p) or i(q) isochromosomes, or into more complex rearrangements when the unstable fragments fuse or rearrange with other chromosomes [Guerrero et al, 2010b;Martinez and van Wely, 2010] ( fig. 2 ).…”

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

“…Merotelic attachments can severely compromise genomic integrity and promote CIN by causing both structural and numerical karyotypic abnormalities. 65 The consequent low-grade aneuploidy is not merely an undesirable-butbenign consequence of cellular transformation but rather a characteristic that actually drives malignancy and tumor evolution. 66 This finding is corroborated by voluminous evidence that centrosome amplification is an early event in carcinogenesis, as it occurs in precancerous and preinvasive lesions.…”

Cancer Genes and Chromosome Instability

“…In contrast, progeny of rarely and spontaneously arising multipolar cell divisions are often unviable undergoing mitotic cell death or cell-cycle arrest [159]. Whole-chromosome segregation errors frequently results in double-strand breaks, which can lead to unbalanced translocations in the daughter cells [163,164] and chromosome pulverization/ chromothripsis defined by small-scale DNA copy number changes and extensive inter-and intrachromosomal rearrangements [165,166]. Structural chromosomal aberrations lead to loss of heterozygosity for tumor suppressor genes [165,[167][168][169][170].…”