PXD024280

PXD024280 is an original dataset announced via ProteomeXchange.

Title	SCAI orchestrates DNA interstrand crosslink repair downstream of FANCI-FANCD2 ubiquitylation
Description	By covalently linking Watson and Crick strands, DNA interstrand crosslinks (ICLs) are highly toxic lesions that block DNA replication and threaten genome integrity. The Fanconi anemia (FA) pathway orchestrates ICL repair during DNA replication, with ubiquitylated FANCI-FANCD2 (ID2) marking the activation step that triggers incisions on one DNA strand to unhook the ICL. ICL unhooking generates a two-ended double-strand break (DSB) on one of the daughter molecules, while leaving a gap comprising the ICL-adduct on the other. Restoration of the adducted molecule by DNA polymerase zeta-mediated translesion synthesis (TLS) creates a template required for repair of the DSB via homologous recombination (HR), but how these processes are coordinated to ensure faithful ICL repair is not known. Here, we uncover a crucial role for SCAI in promoting ICL repair downstream of ID2 activation. Using Xenopus egg extracts and human cells, we show that SCAI forms a complex with DNA polymerase zeta and localizes to ICLs during DNA replication. SCAI-deficient cells are exquisitely sensitive to ICL-inducing drugs and display principal hallmarks of FA gene inactivation, including broken and radial chromosome accumulation. In the absence of SCAI, DSB intermediates are preferentially re-ligated by illegitimate DNA polymerase theta-dependent microhomology-mediated end-joining (MMEJ). Consistently, the hypersensitivity of SCAI-deficient cells to ICLs can be reverted by suppressing FA pathway activation. Our work establishes SCAI as a critical mediator of ICL resolution via the FA pathway, acting at the interphase of the TLS and HR steps to prevent erroneous repair and chromosomal instability.
HostingRepository	PRIDE
AnnounceDate	2022-02-18
AnnouncementXML	Submission_2022-02-18_13:49:48.205.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ivo Hendriks
SpeciesList	scientific name: Xenopus laevis (African clawed frog); NCBI TaxID: 8355;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2021-02-22 01:20:13	ID requested
⏵ 1	2022-02-18 13:49:49	announced

Schubert L, Hendriks IA, Hertz EPT, Wu W, Sell, é, s-Baiget S, Hoffmann S, Viswalingam KS, Gallina I, Pentakota S, Benedict B, Johansen J, Apelt K, Luijsterburg MS, Rasmussen S, Lisby M, Liu Y, Nielsen ML, Mailand N, Duxin JP, SCAI promotes error-free repair of DNA interstrand crosslinks via the Fanconi anemia pathway. EMBO Rep, 23(4):e53639(2022) [pubmed]

submitter keyword: CHROMASS, Xenopus, DNA damage, interstrand crosslink repair, ICL, SCAI, FANCI, FANCD2

Michael Lund Nielsen
contact affiliation	Proteomics program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
contact email	michael.lund.nielsen@cpr.ku.dk
lab head
Ivo Hendriks
contact affiliation	Proteomics program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
contact email	ivo.a.hendriks@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024280
     1. Label: PRIDE project
     2. Name: SCAI orchestrates DNA interstrand crosslink repair downstream of FANCI-FANCD2 ubiquitylation