The ZATT-TOP2A-PICH Axis Drives Extensive Replication Fork Reversal to Promote Genome Stability

Tian, Tian; Bu, Min; Xu, Chong; Ding, Linli; Yang, Yulan; Han, Jie; Feng, Xin‐Hua; Xu, Pinglong; Liu, Ting; Ying, Songmin; Yang, Lei; Li, Qing; Huang, Jun

doi:10.1016/j.molcel.2020.11.007

Cited by 57 publications

(71 citation statements)

References 52 publications

(93 reference statements)

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“…Since simultaneously depletion of SMARCAL1, ZRANB3, and HLTF did not show an additive effect on reversed fork frequency, these three DNA translocases may function at different stages of a common pathway (Taglialatela et al, 2017;Tian et al, 2021). It is also possible that each translocase works preferentially on specific substrates or genomic regions, which need further investigation (Taglialatela et al, 2017;Tian et al, 2021).…”

Section: Critical Enzymes In Fork Slowing and Reversalmentioning

confidence: 99%

Section: A Two-step Mechanism For Replication Fork Reversalmentioning

confidence: 99%

“…Extrusion of the leading and lagging strands from the template DNA during replication fork reversal, catalyzed by the above enzymes, would cause positive superhelical strain in the newly synthesized sister chromatids ( Tian et al, 2021 ). The resulting superhelical strain prevents further regression of the stalled replication forks and must be dissipated by DNA topoisomerases for reversal to proceed efficiently ( Tian et al, 2021 ). Our recent study found that DNA topoisomerase 2 (mainly TOP2A) can release the superhelical strain in newly synthesized chromatids generated by the DNA translocases SMARCAL1, ZRANB3, and HLTF during limited fork reversal ( Tian et al, 2021 ; Figure 2 ).…”

Section: A Two-step Mechanism For Replication Fork Reversalmentioning

confidence: 99%

“…The resulting superhelical strain prevents further regression of the stalled replication forks and must be dissipated by DNA topoisomerases for reversal to proceed efficiently ( Tian et al, 2021 ). Our recent study found that DNA topoisomerase 2 (mainly TOP2A) can release the superhelical strain in newly synthesized chromatids generated by the DNA translocases SMARCAL1, ZRANB3, and HLTF during limited fork reversal ( Tian et al, 2021 ; Figure 2 ). Our study also showed that, with replication stress, TOP2A is SUMOylated by the SUMO E3 ligase ZATT, mainly at lysines 1228 and 1240.…”

Section: A Two-step Mechanism For Replication Fork Reversalmentioning

confidence: 99%

“…Our study also showed that, with replication stress, TOP2A is SUMOylated by the SUMO E3 ligase ZATT, mainly at lysines 1228 and 1240. SUMOylated TOP2A then recruits the SUMO-targeted DNA translocase PICH to stalled replication forks, where PICH branch migrates the Holliday junction structures and drives extensive replication fork reversal ( Tian et al, 2021 ; Figure 2 ). Based on these findings, we proposed that replication fork reversal has two distinct stages, namely initiation and extension stages ( Tian et al, 2021 ; Figure 2 ).…”

Section: A Two-step Mechanism For Replication Fork Reversalmentioning

confidence: 99%

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Replication Fork Reversal and Protection

Qiu

Jiang

Cao

et al. 2021

Front. Cell Dev. Biol.

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During genome replication, replication forks often encounter obstacles that impede their progression. Arrested forks are unstable structures that can give rise to collapse and rearrange if they are not properly processed and restarted. Replication fork reversal is a critical protective mechanism in higher eukaryotic cells in response to replication stress, in which forks reverse their direction to form a Holliday junction-like structure. The reversed replication forks are protected from nuclease degradation by DNA damage repair proteins, such as BRCA1, BRCA2, and RAD51. Some of these molecules work cooperatively, while others have unique functions. Once the stress is resolved, the replication forks can restart with the help of enzymes, including human RECQ1 helicase, but restart will not be considered here. Here, we review research on the key factors and mechanisms required for the remodeling and protection of stalled replication forks in mammalian cells.

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Section: Critical Enzymes In Fork Slowing and Reversalmentioning

confidence: 99%

Section: A Two-step Mechanism For Replication Fork Reversalmentioning

confidence: 99%

Section: A Two-step Mechanism For Replication Fork Reversalmentioning

confidence: 99%

Section: A Two-step Mechanism For Replication Fork Reversalmentioning

confidence: 99%

Section: A Two-step Mechanism For Replication Fork Reversalmentioning

confidence: 99%

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Replication Fork Reversal and Protection

Qiu

Jiang

Cao

et al. 2021

Front. Cell Dev. Biol.

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PTEN‐mediated dephosphorylation of 53BP1 confers cellular resistance to DNA damage in cancer cells

He,

Huang,

Guo

et al. 2023

Molecular Oncology

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Homologous recombination (HR) repair for DNA double‐strand breaks (DSBs) is critical for maintaining genome stability and conferring the resistance of tumor cells to chemotherapy. Nuclear PTEN which contains both phosphatidylinositol 3,4,5‐trisphosphate 3‐phosphatase and protein phosphatase plays a key role in HR repair, but the underlying mechanism remains largely elusive. We find that SUMOylated PTEN promotes HR repair but represses nonhomologous end joining (NHEJ) repair by directly dephosphorylating TP53‐binding protein 1 (53BP1). During DNA damage responses (DDR), tumor suppressor ARF (p14ARF) was phosphorylated and then interacted efficiently with PTEN, thus promoting PTEN SUMOylation as an atypical SUMO E3 ligase. Interestingly, SUMOylated PTEN was subsequently recruited to the chromatin at DSB sites. This was because SUMO1 that was conjugated to PTEN was recognized and bound by the SUMO‐interacting motif (SIM) of breast cancer type 1 susceptibility protein (BRCA1), which has been located to the core of 53BP1 foci on chromatin during S/G2 stage. Furthermore, these chromatin‐loaded PTEN directly and specifically dephosphorylated phosphothreonine‐543 (pT543) of 53BP1, resulting in the dissociation of the 53BP1 complex, which facilitated DNA end resection and ongoing HR repair. SUMOylation‐site‐mutated PTENK254R mice also showed decreased DNA damage repair in vivo. Blocking the PTEN SUMOylation pathway with either a SUMOylation inhibitor or a p14ARF(2‐13) peptide sensitized tumor cells to chemotherapy. Our study therefore provides a new mechanistic understanding of PTEN in HR repair and clinical intervention of chemoresistant tumors.

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