PXD068371-1

PXD068371 is an original dataset announced via ProteomeXchange.

Title	The CIP2A-TOPBP1 axis orchestrates mitotic DNA repair
Description	DNA double-strand breaks (DSBs) accumulate in mitosis in response to DNA replication stress or deficiency in breast cancer susceptibility type 1 and 2 (BRCA1/2). This is a critical threat to genome stability as the classical DSB repair pathways non-homologous end joining (NHEJ) and homologous recombination (HR) are repressed(1-7). Instead, mitotic repair relies on the processes of microhomology-mediated end joining (MMEJ) or mitotic DNA synthesis (MiDAS), but how these pathways are coordinated and regulated remains unclear.  Here, we reveal that the CIP2A-TOPBP1 axis orchestrates DSB repair in mitosis by promoting CDK1-driven phosphorylation of SLX4 at Thr1260, recruiting the SMX complex to promote MiDAS. In addition, the CIP2A-TOPBP1 axis regulates mitotic Polθ recruitment and MMEJ. This dual mechanism ensures coordinated DSBs repair by integrating spatial control of TOPBP1-CIP2A chromatin recruitment with the temporal regulation provided by mitotic kinases, thereby preserving genome stability. These findings provide new insights into DSB repair dynamics in mitosis and offer a mechanistic rationale for the synthetic lethality of CIP2A in BRCA1/2-deficient tumors through the simultaneous impairment of break induced replication (BIR)-like MiDAS and MMEJ, which are genetically redundant pathways to HR.
HostingRepository	PRIDE
AnnounceDate	2025-09-19
AnnouncementXML	Submission_2025-09-19_10:28:07.595.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Graeme Benstead-Hume
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Ascend

Revision	Datetime	Status	ChangeLog Entry
0	2025-09-15 04:07:28	ID requested
⏵ 1	2025-09-19 10:28:08	announced

Dataset with its publication pending

submitter keyword: CIP2A-TOPBP1

Jyoti Choudhary
contact affiliation	functionla proteomics, ICR
contact email	jyoti.choudhary@icr.ac.uk
lab head
Graeme Benstead-Hume
contact affiliation	ICR
contact email	ghume@icr.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD068371
     1. Label: PRIDE project
     2. Name: The CIP2A-TOPBP1 axis orchestrates mitotic DNA repair