Genome stability: What we have learned from cohesinopathies

Abstract

Cohesin is a multiprotein complex involved in many DNA-related processes such as proper chromosome segregation, replication, transcription, and repair. Mutations in cohesin gene pathways are responsible for human diseases, collectively referred to as cohesinopathies. In addition, both cohesin gene expression dysregulation and mutations have been identified in cancer. Cohesinopathy cells are characterized by genome instability (GIN) visualized by a constellation of markers such as chromosome aneuploidies, chromosome aberrations, precocious sister chromatid separation, premature centromere separation, micronuclei formation, and sensitivity to genotoxic drugs. The emerging picture suggests that GIN observed in cohesinopathies may result from the synergistic effects of the multiple cohesin dysfunctions. © 2016 Wiley Periodicals, Inc.

Of Rings and Rods: Regulating Cohesin Entrapment of DNA to Generate Intra- and Intermolecular Tethers

“…Thus, cohesin pathway mutations that deregulate transcription programs produce severe and multispectrum birth defect maladies such as Roberts syndrome (RBS), Cornelia de Lange syndrome (CdLS), and Warsaw breakage syndrome (WBS) (Fig 1) [7–10]. Transcriptional deregulation is also likely to underlie the tight correlation between cohesin mutation and numerous forms of cancer that include aggressive melanoma, leukemia, and breast, astrocytic, and colorectal cancers [11–13].…”

“…Transcriptional deregulation is also likely to underlie the tight correlation between cohesin mutation and numerous forms of cancer that include aggressive melanoma, leukemia, and breast, astrocytic, and colorectal cancers [11–13]. Alternatively, cohesin mutations that abrogate tethering together of sister chromatids results in genotoxic sensitivity, aneuploidy (a hallmark of cancer cells), and apoptotic cell death (which may exacerbate birth defects through proliferative stem cell loss) [7,14–16]. Elucidating the structure through which cohesins bind together DNA segments thus remains of immense interest to both clinical and basic science researchers.…”

An acetyltransferase-independent function of Eso1 regulates centromere cohesion

“…Thus it will be important to understand whether there is a centromeric function for human ESCO1/2, as well as the relationship between the spindle checkpoint and ESCO1/2 (and other cohesin and Smc5/6 components) in the developmental disorders and cancers in which these genes are mutated (Skibbens et al , 2013; Price et al , 2014; Cucco and Musio, 2016; van der Crabben et al , 2016). Indeed, SAC dysfunction may be an explanation as to why some tumor cells can survive loss-of-function mutations in cohesin, whereas normal cells cannot.…”

Cohesin Mutations in Myeloid Malignancies

“…The role of cohesin in regulating sister chromatid cohesion during mitosis has been extensively studied (well reviewed in [23], but the role it plays in regulating gene expression and DNA repair is less well understood. Interestingly, germline mutations in cohesin complex genes lead to chromosomal instability[75], but do not seem to predispose patients to cancer [76]. The study of how germline cohesin mutations contribute to cohesinopathies may provide some insight into possible mechanisms of how somatic cohesin mutations underlie oncogenic processes, including myeloid malignancies.…”