MUS81 promotes common fragile site expression

Songmin Ying; Sheroy Minocherhomji; Kok Lung Chan; Timea Palmai-Pallag; Wai Kit Chu; Theresa Adeline Wass; Hocine W Mankouri; Ying Liu; Ian D Hickson

doi:10.1038/ncb2773

MUS81 promotes common fragile site expression

Songmin Ying, Sheroy Minocherhomji, Kok Lung Chan, Timea Palmai-Pallag, Wai Kit Chu, Theresa Adeline Wass, Hocine W Mankouri, Ying Liu, Ian D Hickson

171 Citations (Scopus)

Abstract

Fragile sites are chromosomal loci with a propensity to form gaps or breaks during early mitosis, and their instability is implicated as being causative in certain neurological disorders and cancers. Recent work has demonstrated that the so-called common fragile sites (CFSs) often impair the faithful disjunction of sister chromatids in mitosis. However, the mechanisms by which CFSs express their fragility, and the cellular factors required to suppress CFS instability, remain largely undefined. Here, we report that the DNA structure-specific nuclease MUS81-EME1 localizes to CFS loci in early mitotic cells, and promotes the cytological appearance of characteristic gaps or breaks observed at CFSs in metaphase chromosomes. These data indicate that CFS breakage is an active, MUS81-EME1-dependent process, and not a result of inadvertent chromatid rupturing during chromosome condensation. Moreover, CFS cleavage by MUS81-EME1 promotes faithful sister chromatid disjunction. Our findings challenge the prevailing view that CFS breakage is a nonspecific process that is detrimental to cells, and indicate that CFS cleavage actually promotes genome stability.

Original language	English
Journal	Nature Cell Biology
Volume	15
Issue number	8
Pages (from-to)	1001-1007
Number of pages	7
ISSN	1465-7392
DOIs	https://doi.org/10.1038/ncb2773
Publication status	Published - Aug 2013

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title = "MUS81 promotes common fragile site expression",

abstract = "Fragile sites are chromosomal loci with a propensity to form gaps or breaks during early mitosis, and their instability is implicated as being causative in certain neurological disorders and cancers. Recent work has demonstrated that the so-called common fragile sites (CFSs) often impair the faithful disjunction of sister chromatids in mitosis. However, the mechanisms by which CFSs express their fragility, and the cellular factors required to suppress CFS instability, remain largely undefined. Here, we report that the DNA structure-specific nuclease MUS81-EME1 localizes to CFS loci in early mitotic cells, and promotes the cytological appearance of characteristic gaps or breaks observed at CFSs in metaphase chromosomes. These data indicate that CFS breakage is an active, MUS81-EME1-dependent process, and not a result of inadvertent chromatid rupturing during chromosome condensation. Moreover, CFS cleavage by MUS81-EME1 promotes faithful sister chromatid disjunction. Our findings challenge the prevailing view that CFS breakage is a nonspecific process that is detrimental to cells, and indicate that CFS cleavage actually promotes genome stability.",

author = "Songmin Ying and Sheroy Minocherhomji and Chan, {Kok Lung} and Timea Palmai-Pallag and Chu, {Wai Kit} and Wass, {Theresa Adeline} and Mankouri, {Hocine W} and Ying Liu and Hickson, {Ian D}",

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doi = "10.1038/ncb2773",

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T1 - MUS81 promotes common fragile site expression

AU - Ying, Songmin

AU - Minocherhomji, Sheroy

AU - Chan, Kok Lung

AU - Palmai-Pallag, Timea

AU - Chu, Wai Kit

AU - Wass, Theresa Adeline

AU - Mankouri, Hocine W

AU - Liu, Ying

AU - Hickson, Ian D

PY - 2013/8

Y1 - 2013/8

N2 - Fragile sites are chromosomal loci with a propensity to form gaps or breaks during early mitosis, and their instability is implicated as being causative in certain neurological disorders and cancers. Recent work has demonstrated that the so-called common fragile sites (CFSs) often impair the faithful disjunction of sister chromatids in mitosis. However, the mechanisms by which CFSs express their fragility, and the cellular factors required to suppress CFS instability, remain largely undefined. Here, we report that the DNA structure-specific nuclease MUS81-EME1 localizes to CFS loci in early mitotic cells, and promotes the cytological appearance of characteristic gaps or breaks observed at CFSs in metaphase chromosomes. These data indicate that CFS breakage is an active, MUS81-EME1-dependent process, and not a result of inadvertent chromatid rupturing during chromosome condensation. Moreover, CFS cleavage by MUS81-EME1 promotes faithful sister chromatid disjunction. Our findings challenge the prevailing view that CFS breakage is a nonspecific process that is detrimental to cells, and indicate that CFS cleavage actually promotes genome stability.

AB - Fragile sites are chromosomal loci with a propensity to form gaps or breaks during early mitosis, and their instability is implicated as being causative in certain neurological disorders and cancers. Recent work has demonstrated that the so-called common fragile sites (CFSs) often impair the faithful disjunction of sister chromatids in mitosis. However, the mechanisms by which CFSs express their fragility, and the cellular factors required to suppress CFS instability, remain largely undefined. Here, we report that the DNA structure-specific nuclease MUS81-EME1 localizes to CFS loci in early mitotic cells, and promotes the cytological appearance of characteristic gaps or breaks observed at CFSs in metaphase chromosomes. These data indicate that CFS breakage is an active, MUS81-EME1-dependent process, and not a result of inadvertent chromatid rupturing during chromosome condensation. Moreover, CFS cleavage by MUS81-EME1 promotes faithful sister chromatid disjunction. Our findings challenge the prevailing view that CFS breakage is a nonspecific process that is detrimental to cells, and indicate that CFS cleavage actually promotes genome stability.

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DO - 10.1038/ncb2773

M3 - Journal article

C2 - 23811685

SN - 1465-7392

VL - 15

SP - 1001

EP - 1007

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 8

ER -

MUS81 promotes common fragile site expression

Abstract

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