PXD023221

PXD023221 is an original dataset announced via ProteomeXchange.

Title	Dual FAN1 activities stabilize the HTT CAG repeat
Description	Recent data strongly suggest HTT CAG repeat expansion drives Huntington’s disease (HD) pathogenesis and that disease development is modulated by components of the DNA damage response (DDR) pathway. FAN1 has been identified as a major HD modifier which slows expansion of the HTT CAG repeat in several cell and animal HD models. Here we show dual FAN1 activities act to inhibit repeat expansion. A highly conserved SPYF motif in the FAN1 N-terminus is required for an MLH1 interaction, which slows expansion, with FAN1 nuclease activity also contributing towards repeat stabilisation. Our data supports a model where FAN1 binds MLH1, restricting its recruitment by MSH3 and the formation of the functional DNA mismatch repair (MMR) complex believed to promote CAG repeat expansion. FAN1 nuclease activity functions either concurrently or following MMR activity to maintain repeat stability. These data highlight a potential avenue for HD therapeutics in attenuating somatic expansion.
HostingRepository	PRIDE
AnnounceDate	2022-02-16
AnnouncementXML	Submission_2022-02-16_10:43:45.174.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Thomas Menneteau
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	SYNAPT G2-Si

Revision	Datetime	Status	ChangeLog Entry
0	2020-12-18 04:59:47	ID requested
⏵ 1	2022-02-16 10:43:46	announced

Goold R, Hamilton J, Menneteau T, Flower M, Bunting EL, Aldous SG, Porro A, Vicente JR, Allen ND, Wilkinson H, Bates GP, Sartori AA, Thalassinos K, Balmus G, Tabrizi SJ, FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease. Cell Rep, 36(9):109649(2021) [pubmed]

submitter keyword: Crosslinking, FAN1

Konstantinos Thalassinos
contact affiliation	Institute of Structural and Molecular Biology, University College London, London, United Kingdom
contact email	k.thalassinos@ucl.ac.uk
lab head
Thomas Menneteau
contact affiliation	Institute of Structural and Molecular Biology - UCL
contact email	t.menneteau@ucl.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD023221
     1. Label: PRIDE project
     2. Name: Dual FAN1 activities stabilize the HTT CAG repeat