RAD54L2 counters TOP2-DNA adducts to promote genome stability

D’Alessandro, Giuseppina; Morales-Juarez, David A.; Richards, Sean L.; Nitiss, Karin C.; Serrano-Benitez, Almudena; Wang, Juanjuan; Thomas, John C.; Gupta, Vipul; Voigt, Andrea; Belotserkovskaya, Rimma; Goh, Chen Gang; Bowden, Anne Ramsay; Galanty, Yaron; Beli, Petra; Nitiss, John L.; Zagnoli-Vieira, Guido; Jackson, Stephen P.

doi:10.1126/sciadv.adl2108

Cited by 6 publications

(1 citation statement)

References 50 publications

(57 reference statements)

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“…ZNF451 therefore has a substantial impact on sensitivity to the TOP2 poison etoposide [ 122 , 149–151 ]. In addition to the SUMO-Ubiquitin dependent clearance of TOP2-DPC and the TDP2 enzymatic removal pathway, SUMOylation of TOP2 and ZNF451 increases their interaction with the ATPase RAD54L2 which can extract the TOP2-DPC from chromatin [ 151 , 152 ]. The SUMO-ubiquitin proteasome-mediated TOP2-DPC clearance pathway promotes DSB formation and sensitivity to etoposide, ultimately leading to genomic instability, suggesting this is not a preferred repair pathway [ 151 , 153 ] ( Figure 9 , subsection 2).…”

Section: Sumoylation and Dna-protein Cross-link Repairmentioning

confidence: 99%

SUMO and the DNA damage response

Bhachoo,

Garvin

2024

Biochemical Society Transactions

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The preservation of genome integrity requires specialised DNA damage repair (DDR) signalling pathways to respond to each type of DNA damage. A key feature of DDR is the integration of numerous post-translational modification signals with DNA repair factors. These modifications influence DDR factor recruitment to damaged DNA, activity, protein-protein interactions, and ultimately eviction to enable access for subsequent repair factors or termination of DDR signalling. SUMO1-3 (small ubiquitin-like modifier 1-3) conjugation has gained much recent attention. The SUMO-modified proteome is enriched with DNA repair factors. Here we provide a snapshot of our current understanding of how SUMO signalling impacts the major DNA repair pathways in mammalian cells. We highlight repeating themes of SUMO signalling used throughout DNA repair pathways including the assembly of protein complexes, competition with ubiquitin to promote DDR factor stability and ubiquitin-dependent degradation or extraction of SUMOylated DDR factors. As SUMO ‘addiction’ in cancer cells is protective to genomic integrity, targeting components of the SUMO machinery to potentiate DNA damaging therapy or exacerbate existing DNA repair defects is a promising area of study.

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Section: Sumoylation and Dna-protein Cross-link Repairmentioning

confidence: 99%

SUMO and the DNA damage response

Bhachoo,

Garvin

2024

Biochemical Society Transactions

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TDP2 is a regulator of estrogen-responsive oncogene expression

Manguso,

Kim,

Joshi

et al. 2024

NAR Cancer

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With its ligand estrogen, the estrogen receptor (ER) initiates a global transcriptional program, promoting cell growth. This process involves topoisomerase 2 (TOP2), a key protein in resolving topological issues during transcription by cleaving a DNA duplex, passing another duplex through the break, and repairing the break. Recent studies revealed the involvement of various DNA repair proteins in the repair of TOP2-induced breaks, suggesting potential alternative repair pathways in cases where TOP2 is halted after cleavage. However, the contribution of these proteins in ER-induced transcriptional regulation remains unclear. We investigated the role of tyrosyl-DNA phosphodiesterase 2 (TDP2), an enzyme for the removal of halted TOP2 from the DNA ends, in the estrogen-induced transcriptome using both targeted and global transcription analyses. MYC activation by estrogen, a TOP2-dependent and transient event, became prolonged in the absence of TDP2 in both TDP2-deficient cells and mice. Bulk and single-cell RNA-seq analyses defined MYC and CCND1 as oncogenes whose estrogen response is tightly regulated by TDP2. These results suggest that TDP2 may inherently participate in the repair of estrogen-induced breaks at specific genomic loci, exerting precise control over oncogenic gene expression.

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Profound synthetic lethality between SMARCAL1 and FANCM

Feng,

Liu,

Shang

et al. 2024

Preprint

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DNA replication stress is a threat to genome integrity. The large SNF2-family of ATPases participates in preventing and mitigating DNA replication stress by employing their ATP-driven motor to remodel DNA or DNA-bound proteins. To understand the contribution of these ATPases in genome maintenance, we undertook CRISPR-based synthetic lethality screens with three SNF2-type ATPases: SMARCAL1, ZRANB3 and HLTF. Here we show that SMARCAL1 displays a profound synthetic lethal interaction with FANCM, another ATP-dependent translocase involved in DNA replication and genome stability. Their combined loss causes severe genome instability that we link to chromosome breakage at loci enriched in simple repeats, which are known to challenge replication fork progression. Our findings illuminate a critical genetic buffering mechanism that provides an essential function for maintaining genome integrity.

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RAD54L2 counters TOP2-DNA adducts to promote genome stability

Cited by 6 publications

References 50 publications

SUMO and the DNA damage response

SUMO and the DNA damage response

TDP2 is a regulator of estrogen-responsive oncogene expression

Profound synthetic lethality between SMARCAL1 and FANCM

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