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The Emerging Role of Cohesin in the DNA Damage Response

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The Emerging Role of Cohesin in the DNA Damage Response G C A T T A C G G C A T genes Review The Emerging Role of Cohesin in the DNA Damage Response Ireneusz Litwin * , Ewa Pilarczyk and Robert Wysocki Institute of Experimental Biology, University of Wroclaw, 50-328 Wroclaw, Poland; [email protected] (E.P.); [email protected] (R.W.) * Correspondence: [email protected]; Tel.: +48-71-375-4126 Received: 29 October 2018; Accepted: 21 November 2018; Published: 28 November 2018 Abstract: Faithful transmission of genetic material is crucial for all organisms since changes in genetic information may result in genomic instability that causes developmental disorders and cancers. Thus, understanding the mechanisms that preserve genome integrity is of fundamental importance. Cohesin is a multiprotein complex whose canonical function is to hold sister chromatids together from S-phase until the onset of anaphase to ensure the equal division of chromosomes. However, recent research points to a crucial function of cohesin in the DNA damage response (DDR). In this review, we summarize recent advances in the understanding of cohesin function in DNA damage signaling and repair. First, we focus on cohesin architecture and molecular mechanisms that govern sister chromatid cohesion. Next, we briefly characterize the main DDR pathways. Finally, we describe mechanisms that determine cohesin accumulation at DNA damage sites and discuss possible roles of cohesin in DDR. Keywords: cohesin; cohesin loader; DNA double-strand breaks; replication stress; DNA damage tolerance 1. Introduction Genomes of all living organisms are continuously challenged by endogenous and exogenous insults that threaten genome stability. It has been estimated that human cells suffer more than 70,000 DNA lesions per day, most of which are single-strand DNA breaks (SSBs) [1]. Moreover, in every human cell ≈50 DNA double-strand breaks (DSBs), considered to be the most cytotoxic DNA lesions, arise during each S-phase through passive conversion of SSBs to DSBs via replication machinery [2–4]. If left unrepaired, such damage may result in chromosome loss and/or cell death. On the other hand, inaccurate repair of DNA damage may lead to point mutations, loss of heterozygosity, or gross chromosomal rearrangements that can drive cancerogenesis [5,6]. To avoid such deleterious outcomes, all eukaryotic cells have evolved DNA damage response (DDR) mechanisms that sense and repair DNA damage or allow them to complete replication of damaged DNA. These include DNA damage checkpoint (DDC), DNA damage repair, and DNA damage tolerance pathways (DDT) [7–9]. Cohesin is a multiprotein, ring-shaped complex that was first characterized in budding yeast Saccharomyces cerevisiae. Its canonical role is to tether sister chromatids together until the onset of anaphase to prevent premature sister chromatid separation and ensure equal segregation of genetic material to daughter cells [10,11]. Moreover, cohesin is crucial for regulation of transcription and 3D chromatin organization [12–14]. However, even before the role of cohesin in sister chromatid cohesion or genome architecture was documented, research on fission yeast Schizosaccharomyces pombe revealed that disruption of cohesin results in increased sensitivity to UV and γ-irradiation [15]. Presently, cohesin is emerging as one of key factors involved in the response to DNA damage. Genes 2018, 9, 581; doi:10.3390/genes9120581 www.mdpi.com/journal/genes GenesGenes 20182018, 9,, 9x, FOR 581 PEER REVIEW 2 of2 of24 24 2. Molecular Architecture of the Cohesin Complex 2. Molecular Architecture of the Cohesin Complex In all eukaryotic organisms, the cohesin complex consists of three core, essential subunits: two structuralIn all maintenance eukaryotic organisms,of chromosome the cohesin proteins complex (SMC), Smc1 consists and of Smc3, three core,and one essential non-SMC subunits: protein, two Scc1structural (RAD21 maintenance in humans). of The chromosome SMC subunits proteins are (SMC),composed Smc1 of andan N-terminal Smc3, and onepart non-SMC containing protein, the WalkerScc1 (RAD21 A motif, in a humans).coiled-coil Theregion SMC separated subunits in arethe composedmiddle by ofa globular an N-terminal domain part called containing the hinge, the andWalker a C-terminal A motif, part a coiled-coil that includes region the separated Walker B inmotif the middle[16]. The by N- a globularand C-terminal domain halves called fold the back hinge, onand themselves a C-terminal to form part intramolecular, that includes theantiparallel Walker B coiled-coils motif [16]. and The functional N- and C-terminal ATPase called halves the fold head back domain.on themselves Smc1 and to formSmc3 intramolecular, interact with each antiparallel other through coiled-coils the hinge and functionaland the head ATPase domains called creating the head andomain. oblong heterodimer. Smc1 and Smc3 Scc1 interact bridges with both each Smc other subunits through by binding the hinge Smc3 and through the head its domains N-terminal creating part an andoblong by interacting heterodimer. with Scc1 Smc1 bridges via its both C-terminus Smc subunits (Figure by 1). binding Together, Smc3 Smc1, through Smc3, its N-terminal and Scc1 create partand a ring-likeby interacting structure with that Smc1 is about via its 50 C-terminus nm long (Figurewith a1 ≈).35 Together, nm diameter Smc1, [17–20]. Smc3, and In Scc1addition, create there a ring-like are severalstructure other that proteins is about that 50 nmassociate long with with a ≈the35 co nmhesin diameter ring, [including17–20]. In two addition, essential there HEAT are several proteins, other Scc3proteins (SA1 and that SA2 associate in humans) with the and cohesin Pds5 ring,(PDS5A including and PDS5B two essentialin humans), HEAT that proteins, interact Scc3 with (SA1 the C- and terminalSA2 in and humans) the N-terminal and Pds5 (PDS5Apart of Scc1, and respecti PDS5B invely, humans), and Wpl1 that (WAPL interact in with humans), the C-terminal which is a and non- the essential,N-terminal unstably part of bound Scc1, respectively, protein that and interacts Wpl1 (WAPLwith cohesin in humans), through which Scc3, is aPds5, non-essential, Scc1, and unstably Smc3 (Figurebound 1) protein [21–24]. that interacts with cohesin through Scc3, Pds5, Scc1, and Smc3 (Figure1)[21–24]. FigureFigure 1. 1.TheThe cohesin cohesin complex. complex. Cohesin Cohesin is iscomposed composed of ofSmc1 Smc1 and and Smc3 Smc3 proteins proteins that that contain contain two two globularglobular domains, domains, called called the the hinge hinge and and the the head, head, separated separated by by a long a long coiled-coil coiled-coil domain. domain. Smc1 Smc1 and and Smc3Smc3 interact interact with with each each other other through through the the hinge hinge and and the the head head domains. domains. Th Thee hinge hinge domain domain is isthe the possiblepossible entry entry gate gate for for the the DNA DNA while while the the head head is isan an ATPase. ATPase. Scc1 Scc1 binds binds Smc3 Smc3 and and Smc1 Smc1 with with its itsN- N- andand C-terminus, C-terminus, respectively, respectively, completing completing the the cohesin cohesin ring. ring. Pds5 Pds5 and and Scc3 Scc3 are are stably stably bound bound cohesin cohesin subunitssubunits that that interact interact with with cohesin cohesin through Scc1.Scc1. Wpl1Wpl1binds binds to to cohesin cohesin only only temporarily temporarily through through Scc3, Scc3,Pds5, Pds5, Scc1, Scc1, and and Smc3. Smc3. 3. 3.Sister Sister Chromatid Chromatid Cohesion Cohesion Process Process 3.1. Cohesin Loading 3.1. Cohesin Loading The first stage of the sister chromatid cohesion process is cohesin loading. In S. cerevisiae, cohesin The first stage of the sister chromatid cohesion process is cohesin loading. In S. cerevisiae, cohesin binding to chromatin starts in late G1/early S-phase when Scc1 expression is reinduced [25,26]. binding to chromatin starts in late G1/early S-phase when Scc1 expression is reinduced [25,26]. In In humans, on the other hand, intact cohesins, that were deposited by WAPL in prophase, associate humans, on the other hand, intact cohesins, that were deposited by WAPL in prophase, associate with chromatin in telophase [27,28]. Both in yeast and humans, cohesin loading depends on the with chromatin in telophase [27,28]. Both in yeast and humans, cohesin loading depends on the Scc2– Scc2–Scc4 cohesin loading complex (NIPBLA- or NIPBLB-MAU2 in humans) that allows entrapment of Scc4 cohesin loading complex (NIPBLA- or NIPBLB-MAU2 in humans) that allows entrapment of GenesGenes 20182018, ,99, ,x 581 FOR PEER REVIEW 3 3of of 24 24 sister chromatids inside the cohesin ring [20,26,29–32]. Scc2 is a large protein (171 kDa) that contains N-sister and chromatids C-terminal inside globular the domains cohesin ring separated [20,26, 29by– 32HEAT]. Scc2 repeats is a large [33]. protein Scc4 is (171 a smaller kDa) that protein contains (72 kDa)N- and that C-terminal consists mostly globular of domainsTPR (tetratricopeptide separated by HEAT repeat) repeats structural [33]. Scc4motifs is a[34]. smaller It has protein been (72shown, kDa) boththat consistsin humans mostly and ofin TPRyeast, (tetratricopeptide that Scc4 binds to repeat) the unstructured structural motifs N-terminal [34]. It haspart been of Scc2, shown, creating both ina stable,humans heterodimeric and in yeast, hook-shaped that Scc4 binds complex to the (Figure unstructured 2) [34–36]. N-terminal part of Scc2, creating a stable, heterodimeric hook-shaped complex (Figure2)[34–36]. FigureFigure 2. 2. PossiblePossible cohesin cohesin cycle cycle in in yeast. yeast. In In the the G1 G1 phase phase of of the the cell cell cycle, cycle, the the cohesin cohesin complex complex does does notnot form form because because Scc1 Scc1 is is absent absent ( (AA).). In In the the late late G1/early G1/early S-phase S-phase Scc1 Scc1 expression expression is is reinduced reinduced allowing allowing formationformation of of the the complete complete cohesin cohesin complex.
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