Haploinsufficiency ofSGO1results in deregulated centrosome dynamics, enhanced chromosomal instability and colon tumorigenesis

Abstract

Since its discovery several years ago, Shugoshin 1 (SGO1) has emerged as a crucial regulator of the cell cycle. [1][2][3][4][5][6] At cellular and molecular levels, SGO1 functions as a protector of centromeric cohesion of sister chromatids in higher eukaryotes. [5][6][7] Depletion of SGO1 by small interfering RNA (siRNA) leads to premature sister chromatid separation. [5][6][7][8] During mitosis, SGO1 localizes to centromeres in a manner that appears to be dependent on Bub1, Aurora B and survivin.7-13 SGO1 works in concert with protein phosphatase 2A (PP2A) to protect centromeric cohesion during mitosis and meiosis. 14,15 It is implicated in microtubule dynamics and required for tension generation at the kinetochore. 2,6 In addition to the function of SGO1 in centromeres, sSGO1, a major splice variant of SGO1, has an important function in centrosome dynamics through mediating centriole cohesion. 16 A recent study supports the centrosomal function of Sgo1 in further detail. 17Importantly, both cohesin and Sgo1 are shown to be involved in engagement of centrioles and thus in centrosomal integrity. 17Given the importance of centromeric cohesion and centrosome Chromosome instability (CIN) is found in 85% of colorectal cancers. Defects in mitotic processes are implicated in high CIN and may be critical events in colorectal tumorigenesis. Shugoshin-1 (SGO1) aids in the maintenance of chromosome cohesion and prevents premature chromosome separation and CIN. In addition, integrity of the centrosome may be compromised due to the deficiency of Cohesin and Sgo1 through the disengagement of centrioles. We report here the generation and characterization of SGO1-mutant mice and show that haploinsufficiency of SGO1 leads to enhanced colonic tumorigenesis. Complete disruption of SGO1 results in embryonic lethality, whereas SGO1 +/-mice are viable and fertile. Haploinsufficiency of SGO1 results in genomic instability manifested as missegregation of chromosomes and formation of extra centrosomal foci in both murine embryonic fibroblasts and adult bone marrow cells. enhanced CIN observed in SGO1-deficient mice resulted in an increase in formation of aberrant crypt foci (ACF) and accelerated development of tumors after exposure to azoxymethane (AoM), a colon carcinogen. together, these results suggest that haploinsufficiency of SGO1 causes enhanced CIN, colonic preneoplastic lesions and tumorigenesis in mice. SGO1 is essential for the suppression of CIN and tumor formation. Key words: SGO1, mouse genetics, chromosomal instability, centrosome, colon cancer Abbreviations: SGO1, shugoshin 1; CIN, chromosome instability; AOM, azoxymethane; siRNA, small interfering RNA; MEFs, mouse embryonic fibroblasts; FACS, fluorescence activated cell sorter; ACF, aberrant crypt foci; WT, wild type; COX2, cyclooxygenase-2 dynamics in the maintenance of chromosomal stability during cell division, it is conceivable that deregulated function of SGO1 would lead to major chromosomal instability. Chromosomal instability has long been appreciated as a drivi...

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

“…The Sgo1 −/+ haploinsufficient mouse is a model that displays two direct effects of a reduction in Sgo1, both of which lead to prolonged mitosis via the spindle checkpoint: (a) cohesinopathy in mitotic chromosome; and (b) defects in centrosome integrity (Yamada et al., 2012). Whether the AD pathology is caused by cohesinopathy, centrosome defect, or the common consequence that is prolonged mitosis must be distinguished.…”

“…C57BL/6‐based wild‐type (WT), Sgo1 −/+ (Rao et al., 2016; Yamada et al., 2012, 2015, 2016), and BubR1 −/+ (Dai et al., 2004; Rao et al., 2005) mice were bred and maintained in a pathogen‐free rodent barrier facility without treatment for 24–25 months (an observational study). Surviving animals were euthanized and organs were collected following our standard operating procedures (Yamada et al., 2012).…”

“…A likely reason for the rarity of CAID syndrome is that congenital mutation in human SgoL1 may not be compatible with early development. In mouse, Sgo1 is highly expressed in heart, gut, and CNS during early development (Song et al., 2017a, 2017b), and Sgo1 −/− (knockout) is embryonic lethal (Yamada et al., 2012); strongly suggesting essential function of Sgo1 and SgoL1 during early development. Also, this study is the first ever study linking Sgo1 and AD.…”

“…Cohesins keep sister chromatids from prematurely separating during mitosis, thus ensuring mitotic fidelity (Hirano, 2015). The Sgo1 haploinsufficient (∓) mouse is a model of cohesinopathy and chromosome instability (CIN) (Rao et al., 2016; Wang et al., 2008; Yamada et al., 2012, 2015, 2016). Sgo1 −/+ model has shown unique transcriptomic signatures at the tissue/organ level and cancer proneness in certain organs including colon, lung, and liver (Rao et al., 2016; Yamada et al., 2012, 2015, 2016).…”

“…The Sgo1 haploinsufficient (∓) mouse is a model of cohesinopathy and chromosome instability (CIN) (Rao et al., 2016; Wang et al., 2008; Yamada et al., 2012, 2015, 2016). Sgo1 −/+ model has shown unique transcriptomic signatures at the tissue/organ level and cancer proneness in certain organs including colon, lung, and liver (Rao et al., 2016; Yamada et al., 2012, 2015, 2016). In humans, the homolog SgoL1 is frequently mutated or abnormally expressed in cancers, affecting the mitotic process (Iwaizumi et al., 2009; Kahyo et al., 2011; Matsuura et al., 2013; Wang et al., 2015).…”