Last update 19 Sep 2024

FANCI

Last update 19 Sep 2024

Basic Info

Synonyms

FA complementation group I, FANCI, Fanconi anemia group I protein

+ [3]

Introduction

Plays an essential role in the repair of DNA double-strand breaks by homologous recombination and in the repair of interstrand DNA cross-links (ICLs) by promoting FANCD2 monoubiquitination by FANCL and participating in recruitment to DNA repair sites. Required for maintenance of chromosomal stability. Specifically binds branched DNA: binds both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA). Participates in S phase and G2 phase checkpoint activation upon DNA damage.

Drugs associated with FANCI

RNA splicing modulators (Skyhawk)

Target

FANCI x FANCL

Mechanism

FANCI modulators [+2]

Active Org.

Skyhawk Therapeutics, Inc.Startup [+1]

Originator Org.

Skyhawk Therapeutics, Inc.Startup

Active Indication

Multiple Myeloma [+3]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with FANCI

100 Translational Medicine associated with FANCI

0 Patents (Medical) associated with FANCI

321

Literatures (Medical) associated with FANCI

01 Sep 2024·International Journal of Surgical Pathology

Loss of Histone H3K27 Trimethylation (H3K27me3) Expression as a Potential Diagnostic Pitfall in Sarcomatoid Carcinoma

Article

Author: Zilla, Megan L ; Naous, Rana ; John, Ivy

Loss of histone H3K27 Trimethylation (H3K27me3) immunohistochemical expression is commonly used as an ancillary test and a surrogate marker for the diagnosis of malignant peripheral nerve sheath tumor (MPNST). A potential histological mimic of MPNST is sarcomatoid carcinoma. Prompted by an index specimen of sarcomatoid carcinoma with H3K27me3 loss and the lack of literature on such phenomenon, we sought to determine the frequency of H3K27me3 loss of expression in a cohort of sarcomatoid carcinomas. Fifty specimens of primary and metastatic sarcomatoid carcinomas with spindle cell morphology mimicking MPNST were prospectively and retrospectively retrieved from our institutional archives and stained with an antibody to H3K27me3. H3K27me3 staining was lost in 4 of the 50 specimens (8%). These specimens included a primary sarcomatoid urothelial carcinoma of the bladder resection, two local recurrences (sarcomatoid squamous cell carcinoma of the larynx and oral cavity) as well as a metastatic sarcomatoid renal cell carcinoma. Next-generation sequencing performed on all four specimens demonstrated gene mutations and copy number alterations with TP53, FANC ( FANCD2 and FANCI), and TERT being the most common gene mutations and CDKN2A/B copy number loss and 11q region amplification being the most common copy number gene alterations. Mutations involving NF1, SUZ12, or EED were absent in all tested specimens. In conclusion, H3K27me3 expression may be lost in as many as 8% of sarcomatoid carcinomas which can pose as a potential diagnostic pitfall, especially in challenging sarcomatoid carcinoma specimens with absent keratin staining.

29 Aug 2024·Nature

FANCD2–FANCI surveys DNA and recognizes double- to single-stranded junctions

Article

Author: McLaughlin, Stephen H ; Sale, Julian E ; Alcón, Pablo ; Guilbaud, Guillaume ; Ray, Korak Kumar ; Knipscheer, Puck ; Liolios, Themistoklis ; Rueda, David S ; Shen, Yichao ; Kaczmarczyk, Artur P ; Sijacki, Tamara ; Passmore, Lori A

AbstractDNA crosslinks block DNA replication and are repaired by the Fanconi anaemia pathway. The FANCD2–FANCI (D2–I) protein complex is central to this process as it initiates repair by coordinating DNA incisions around the lesion1. However, D2–I is also known to have a more general role in DNA repair and in protecting stalled replication forks from unscheduled degradation2–4. At present, it is unclear how DNA crosslinks are recognized and how D2–I functions in replication fork protection. Here, using single-molecule imaging, we show that D2–I is a sliding clamp that binds to and diffuses on double-stranded DNA. Notably, sliding D2–I stalls on encountering single-stranded–double-stranded (ss–ds) DNA junctions, structures that are generated when replication forks stall at DNA lesions5. Using cryogenic electron microscopy, we determined structures of D2–I on DNA that show that stalled D2–I makes specific interactions with the ss–dsDNA junction that are distinct from those made by sliding D2–I. Thus, D2–I surveys dsDNA and, when it reaches an ssDNA gap, it specifically clamps onto ss–dsDNA junctions. Because ss–dsDNA junctions are found at stalled replication forks, D2–I can identify sites of DNA damage. Therefore, our data provide a unified molecular mechanism that reconciles the roles of D2–I in the recognition and protection of stalled replication forks in several DNA repair pathways.

05 Jul 2024·The Oncologist

Clinical actionability of BRCA2 alterations in uterine leiomyosarcoma: a molecular tumor board case report and a cBioPortal comprehensive analysis

Article

Author: Parma, Gabriella ; Curigliano, Giuseppe ; Fusco, Nicola ; Marra, Antonio ; Belli, Carmen ; Crimini, Edoardo ; Colombo, Nicoletta ; Repetto, Matteo ; Setola, Elisabetta ; Boscolo Bielo, Luca ; Guerini Rocco, Elena ; Barberis, Massimo

AbstractBackgroundUterine leiomyosarcoma (uLMS) represents one of the most common sarcoma histotypes, demonstrating an overall dismal prognosis. Previous studies reported uLMS to carry recurrent somatic BRCA2 homozygous deletions, related to significant clinical benefits from the use of PARP inhibitors.MethodsTo investigate the prevalence in uLMS of genomic alterations (alt) in BRCA2 and other homologous recombination (HR) and DNA damage response (DDR) genes, cBioPortal was accessed and data were retrieved from studies including pan-sarcoma histologies. HR-/DDR-genes included BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, NBN, PALB2, RAD51C, RAD51D, RAD50, and ATR. Only oncogenic/likely oncogenic alterations were included according to OncoKB.Clinical Report and ResultsWe reported a clinical case of a patient affected by a highly pretreated uLMS discussed at the European Institute of Oncology Molecular Tumor Board. A targeted next-generation sequencing panel demonstrated a somatic BRCA2 homozygous deletion (homDel). Upon access to Niraparib, a remarkable response of 15 months was observed before experiencing disease progression. In the genomic query, among 2393 cases, uLMS (n = 193) displayed 9 of all 31 BRCA2alt observed, representing the only sarcoma histotype showing an enrichment in BRCA2alt (4.66%; q < 0.001). All of 9 BRCA2alt were represented by homDel, which related to a high fraction of genome altered.ConclusionuLMS displays a significant frequency of somatic BRCA2alt homDel. Considering their dismal prognosis, further investigation is warranted to test the use of PARPi in uLMS, and particularly in the setting of BRCA1/2 alterations.

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FANCI

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