The nuclear kinesin KIF18B promotes 53BP1-mediated DNA double-strand break repair

Luessing, Janna; Sakhteh, Maryam; Sarai, Naoyuki; Frizzell, Louise; Tsanov, Nikolay; Ramberg, Kiefer O.; Maretto, Silvia; Crowley, Peter B.; Lowndes, Noel F.

doi:10.1016/j.celrep.2021.109306

Cited by 15 publications

(23 citation statements)

References 52 publications

(78 reference statements)

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“…As discussed, its role in slow-kinetic cNHEJ is not just limited to inhibition of resection but it may also have active roles in slowkinetic cNHEJ (e.g., recruitment of Artemis, CST-Polα-primase), while in HR 53BP1 promotes fidelity by preventing excessive resection (Wang et al, 2014;Ochs et al, 2016;Löbrich and Jeggo, 2017;Mirman et al, 2018;Zhao et al, 2020;Kelich et al, 2021). Given such important roles, it is not surprising that 53BP1 recruitment is tightly regulated by multiple additional mechanisms: 1) the Tudor interacting repair regulator (TIRR) can bind the Tudor domain of 53BP1 to block its H4K20me2 binding (Drané et al, 2017;Dai et al, 2018;Wang et al, 2018); 2) acetylation within the 53BP1 UDR domain (K1626/K1628) by CREB-binding protein (CBP) disrupts 53BP1 binding to the nucleosome (Guo et al, 2018); 3) RNF169, an RNF168 paralogue, appears to be able to antagonise 53BP1, as well as RAP80-BRCA1, accumulation at DSBs through a mechanism that remains enigmatic (Chen et al, 2012;Panier et al, 2012;Poulsen et al, 2012;An et al, 2018); 4) phosphorylation of the damage dependent H2AK15 ubiquitin tag (UbT12p) itself also inhibits binding of 53BP1, but not HR factors (Walser et al, 2020); intriguingly, and in contrast to these negative regulatory mechanisms, 53BP1 binding can be positively regulated by the kinesin, KIF18B, in a mechanism requiring a direct interaction with the 53BP1 Tudor domain and the motor activity of KIF18B (Luessing et al, 2021).…”

Section: The Role Of 53bp1 and Brca1 In The Late Double Strand Break Responsementioning

confidence: 99%

Immediate-Early, Early, and Late Responses to DNA Double Stranded Breaks

Kieffer

Lowndes

2022

Front. Genet.

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Loss or rearrangement of genetic information can result from incorrect responses to DNA double strand breaks (DSBs). The cellular responses to DSBs encompass a range of highly coordinated events designed to detect and respond appropriately to the damage, thereby preserving genomic integrity. In analogy with events occurring during viral infection, we appropriate the terms Immediate-Early, Early, and Late to describe the pre-repair responses to DSBs. A distinguishing feature of the Immediate-Early response is that the large protein condensates that form during the Early and Late response and are resolved upon repair, termed foci, are not visible. The Immediate-Early response encompasses initial lesion sensing, involving poly (ADP-ribose) polymerases (PARPs), KU70/80, and MRN, as well as rapid repair by so-called ‘fast-kinetic’ canonical non-homologous end joining (cNHEJ). Initial binding of PARPs and the KU70/80 complex to breaks appears to be mutually exclusive at easily ligatable DSBs that are repaired efficiently by fast-kinetic cNHEJ; a process that is PARP-, ATM-, 53BP1-, Artemis-, and resection-independent. However, at more complex breaks requiring processing, the Immediate-Early response involving PARPs and the ensuing highly dynamic PARylation (polyADP ribosylation) of many substrates may aid recruitment of both KU70/80 and MRN to DSBs. Complex DSBs rely upon the Early response, largely defined by ATM-dependent focal recruitment of many signalling molecules into large condensates, and regulated by complex chromatin dynamics. Finally, the Late response integrates information from cell cycle phase, chromatin context, and type of DSB to determine appropriate pathway choice. Critical to pathway choice is the recruitment of p53 binding protein 1 (53BP1) and breast cancer associated 1 (BRCA1). However, additional factors recruited throughout the DSB response also impact upon pathway choice, although these remain to be fully characterised. The Late response somehow channels DSBs into the appropriate high-fidelity repair pathway, typically either ‘slow-kinetic’ cNHEJ or homologous recombination (HR). Loss of specific components of the DSB repair machinery results in cells utilising remaining factors to effect repair, but often at the cost of increased mutagenesis. Here we discuss the complex regulation of the Immediate-Early, Early, and Late responses to DSBs proceeding repair itself.

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Section: The Role Of 53bp1 and Brca1 In The Late Double Strand Break Responsementioning

confidence: 99%

Immediate-Early, Early, and Late Responses to DNA Double Stranded Breaks

Kieffer

Lowndes

2022

Front. Genet.

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“…Kinesin family member 18B (KIF18B) is another member of kinesin that localizes to the nucleus and binds to chromatin throughout the interphase [149]. Most recently, KIF18B, which is also recruited to the sites of DSBs, was reported to be required for 53BP1-mediated DSB repair [150]. This study demonstrated that the ability of KIF18B to bind 53BP1, as well as its motor function is required for efficient 53BP1-mediated end-joining of DSBs.…”

Section: Kif18bmentioning

confidence: 92%

Molecular Link between DNA Damage Response and Microtubule Dynamics

Kim

2022

IJMS

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Microtubules are major components of the cytoskeleton that play important roles in cellular processes such as intracellular transport and cell division. In recent years, it has become evident that microtubule networks play a role in genome maintenance during interphase. In this review, we highlight recent advances in understanding the role of microtubule dynamics in DNA damage response and repair. We first describe how DNA damage checkpoints regulate microtubule organization and stability. We then highlights how microtubule networks are involved in the nuclear remodeling following DNA damage, which leads to changes in chromosome organization. Lastly, we discuss how microtubule dynamics participate in the mobility of damaged DNA and promote consequent DNA repair. Together, the literature suggests the importance of microtubule dynamics in genome organization and stability during interphase.

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“…Since microtubules and kinesins have been linked to the repair of DSBs 12,14 , we sought to determine if MAP7 and MAP7D1 affect the repair of DNA damage caused by γ-irradiation.…”

Section: Downregulation Of Map7 and Map7d1 Leads To Defects In Dna Re...mentioning

confidence: 99%

“…Moreover, KIF18B and KIF2C, two kinesins which act as motor proteins on microtubules, are involved in DSB repair 14,15 . Nevertheless, the scale of processes through which microtubules affect DDR, the number of cytoskeleton-related proteins involved in DDR and the exact molecular mechanisms behind these processes remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Microtubule-associated proteins MAP7 and MAP7D1 promote DNA double strand break repair in the G1 cell cycle phase

Dullovi

Ozgencil

Tse

et al. 2023

Preprint

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The DNA-damage response is a complex signalling network that guards genomic integrity. The microtubule cytoskeleton is involved in the repair of DNA double-strand breaks; however, little is known about which cytoskeleton-related proteins are involved in DNA repair and how. Using quantitative proteomics, we discovered that microtubule associated proteins MAP7 and MAP7D1 interact with several DNA repair proteins including DNA double-strand break repair proteins RAD50, BRCA1 and 53BP1. We observed that downregulation of MAP7 and MAP7D1 leads to increased phosphorylation of p53 after gamma-irradiation. Moreover, we determined that the downregulation of MAP7D1 leads to a strong G1 arrest and that the downregulation of MAP7 and MAP7D1 in cells arrested in G1 negatively affects DNA repair, recruitment of RAD50 to chromatin and localisation of 53BP1 to the sites of damage. These findings describe for the first time a novel function of MAP7 and MAP7D1 in cell cycle regulation and cellular response to DNA double-strand breaks.

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The nuclear kinesin KIF18B promotes 53BP1-mediated DNA double-strand break repair

Cited by 15 publications

References 52 publications

Immediate-Early, Early, and Late Responses to DNA Double Stranded Breaks

Immediate-Early, Early, and Late Responses to DNA Double Stranded Breaks

Molecular Link between DNA Damage Response and Microtubule Dynamics

Microtubule-associated proteins MAP7 and MAP7D1 promote DNA double strand break repair in the G1 cell cycle phase

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