53BP1 and the LINC Complex Promote Microtubule-Dependent DSB Mobility and DNA Repair

Lottersberger, Francisca; Karssemeijer, Roos A.; Dimitrova, Nadya; Lange, Titia de

doi:10.1016/j.cell.2015.09.057

Cited by 258 publications

(357 citation statements)

References 57 publications

(92 reference statements)

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“…[5][6][7][8][9] LINC complexes and nuclear lamins form a solid scaffold for diverse functions including nuclear migration, 10 nuclear shaping and positioning,. 11,12 maintaining the centrosome-nucleus connection, 13,14 mechanotransduction, 15,16 DNA repair, 17,18 nuclear membrane spacing, cancer, and recessive cerebellar ataxia. 25,26,27 However, for several reasons, it is not known how cells regulate these multiple LINC complex functions.…”

Section: Introductionmentioning

confidence: 99%

SUN1 splice variants, SUN1_888, SUN1_785, and predominant SUN1_916, variably function in directional cell migration

Nishioka

Imaizumi

Imada

et al. 2016

Nucleus

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The LINC complex is a multifunctional protein complex that is involved in various processes at the nuclear envelope, such as nuclear migration, mechanotransduction and chromatin tethering in the meiotic phase. However, it remains unknown how these functions are regulated in different cell contexts. An inner nuclear membrane component of the LINC complex, SUN1, is ubiquitously expressed. The human SUN1 gene produces over 10 variants by alternative splicing. Although functions of SUN1 are relatively well characterized, functional differences among SUN1 splice variants are poorly characterized. LINC complex components are associated with a wide range of human diseases; therefore, it is important to understand the functional diversity among SUN1 splice variants. Here, we identified a novel human SUN1 splice variant, SUN1_888. overexpression of the SUN1 splice variants, SUN1_888 or SUN1_785, but not the predominant isoform, SUN1_916, activated directional cell migration. Knockdown of SUN1_888 suppressed cell migration; in contrast depletion of SUN1_916 activated cell migration. In addition, all of investigated SUN1 splicing variants rescued cell migration in SUN1 knock out cell. These results indicate that redundant and non-redundant functions of SUN1 splice variant in directional cell migration and suggest that variable LINC complexes with distinct task may exit. Furthermore, in contrast to previous studies, we showed association between SUN1 and B-type lamins. Interestingly, B-type lamin preferentially interacts with SUN1 but not SUN2. These results suggest that tissue-specific SUN1 variants variably interact with nucleoplasmic partners and allow variable assembly of LINC complexes that can be assigned to distinct tasks.

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Section: Introductionmentioning

confidence: 99%

SUN1 splice variants, SUN1_888, SUN1_785, and predominant SUN1_916, variably function in directional cell migration

Nishioka

Imaizumi

Imada

et al. 2016

Nucleus

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“…This system has allowed the identification of several novel aspects of the DDR (Zimmermann et al 2013;Lottersberger et al 2015;Kibe et al 2016). Here we used dysfunctional telomeres to identify PHF11 (plant homeodomain finger 11) as a DDR factor.…”

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confidence: 99%

PHF11 promotes DSB resection, ATR signaling, and HR

et al. 2017

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Resection of double-strand breaks (DSBs) plays a critical role in their detection and appropriate repair. The 3 ′ ssDNA protrusion formed through resection activates the ATR-dependent DNA damage response (DDR) and is required for DSB repair by homologous recombination (HR). Here we report that PHF11 (plant homeodomain finger 11) encodes a previously unknown DDR factor involved in 5 ′ end resection, ATR signaling, and HR. PHF11 was identified based on its association with deprotected telomeres and localized to sites of DNA damage in S phase. Depletion of PHF11 diminished the ATR signaling response to telomere dysfunction and genome-wide DNA damage, reduced end resection at sites of DNA damage, resulted in compromised HR and misrejoining of S-phase DSBs, and increased the sensitivity to DNA-damaging agents. PHF11 interacted with the ssDNA-binding protein RPA and was found in a complex with several nucleases, including the 5 ′ dsDNA exonuclease EXO1. Biochemical experiments demonstrated that PHF11 stimulates EXO1 by overcoming its inhibition by RPA, suggesting that PHF11 acts (in part) by promoting 5 ′ end resection at RPA-bound sites of DNA damage. These findings reveal a role for PHF11 in DSB resection, DNA damage signaling, and DSB repair.[Keywords: PHF11; EXO1; RPA; ATR; DSB; resection; homologous recombination] Supplemental material is available for this article.Received October 9, 2016; revised version accepted December 22, 2016.Nuclear double-strand breaks (DSBs) activate the ATM and ATR kinase-dependent DNA damage response (DDR) pathways (for review, see Ciccia and Elledge 2010). Whereas the ATM kinase responds to the presence of dsDNA ends, activation of the ATR kinase requires the presence of ssDNA that is bound by RPA. In addition, activation of the ATR kinase requires the loading of the 9-1-1 complex on the double-stranded-single-stranded junction formed after 5 ′ end resection. Resection of the 5 ′ end of DSBs is therefore a critical step in the activation of ATR signaling. DSB resection is also required for the initiation of several DNA repair pathways, including homologous recombination (HR) and single-strand annealing (SSA) (for review, see Symington and Gautier 2011). HR can restore the original DNA sequence using the sister chromatid as a template for repair. After 5 ′ end resection, HR is initiated by the BRCA2-mediated loading of the Rad51 recombinase onto the ssDNA. In the absence of HR, S-phase DSBs can become a substrate for more error-prone DSB repair, including SSA and classical or alternative nonhomologous end-joining (NHEJ). DSB resection is initiated through the agency of BRCA1, the MRE11/RAD50/NBS1 (MRN) complex, and CtIP (for review, see Cejka 2015). The outcome is a ssDNA end with a short (∼20-nucleotide [nt]) 3 ′ overhang that is a substrate for further nucleolytic attack by EXO1, a dsDNA exonuclease that degrades only the 5 ′ strand to leave a 3 ′ overhang that can be thousands of nucleotides in length. In addition, an overlapping pathway involving the DNA2 nuclease acting in conjun...

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“…53BP1 also functions in both heterochromatin relaxation (Ziv et al, 2006;Goodarzi et al, 2008) (see below) and chromatin mobility at DSBs. This chromatin mobility function of 53BP1 is mediated in combination with the linker of nucleoskeleton and cytoskeleton (LINC) complex and microtubules (Lottersberger et al, 2015). The mechanism involved in the mobility of the ends of DSBs functions in C-NHEJ at dysfunctional telomeres (Dimitrova et al, 2008) (see below), class switch recombination (Manis et al, 2004;Ward et al, 2004;Reina-San-Martin et al, 2007) and long-range joining of V(D)J recombination (Difilippantonio et al, 2008).…”

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confidence: 99%

The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks

Muraki

Murnane

2017

Genes Genet. Syst.

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In mammals, DNA double-strand breaks (DSBs) are primarily repaired by classical non-homologous end joining (C-NHEJ), although homologous recombination repair and alternative NHEJ (A-NHEJ), which involve DSB processing, can also occur. These pathways are tightly regulated to maintain chromosome integrity. The ends of chromosomes, called telomeres, contain telomeric DNA that forms a cap structure in cooperation with telomeric proteins to prevent the activation of the DNA damage response and chromosome fusion at chromosome termini. Telomeres and subtelomeric regions are poor substrates for DNA replication; therefore, regions near telomeres are prone to replication fork stalling and chromosome breakage. Moreover, DSBs near telomeres are poorly repaired. As a result, when DSBs occur near telomeres in normal cells, the cells stop proliferating, while in cancer cells, subtelomeric DSBs induce rearrangements due to the absence of cell cycle checkpoints. The sensitivity of subtelomeric regions to DSBs is due to the improper regulation of processing, because although C-NHEJ is functional at subtelomeric DSBs, excessive processing results in an increased frequency of large deletions and chromosome rearrangements involving A-NHEJ.

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53BP1 and the LINC Complex Promote Microtubule-Dependent DSB Mobility and DNA Repair

Cited by 258 publications

References 57 publications

SUN1 splice variants, SUN1_888, SUN1_785, and predominant SUN1_916, variably function in directional cell migration

SUN1 splice variants, SUN1_888, SUN1_785, and predominant SUN1_916, variably function in directional cell migration

PHF11 promotes DSB resection, ATR signaling, and HR

The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks

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