Reference Detail

Ref Type

Journal Article

PMID

(32542039)

Authors

Odermatt DC, Lee WTC, Wild S, Jozwiakowski SK, Rothenberg E, Gari K

Title

Cancer-associated mutations in the iron-sulfur domain of FANCJ affect G-quadruplex metabolism.

Journal	Vol	Issue	Date	Pages	Journal Short Title
PLoS genetics	16	6	2020 06	e1008740	PLoS Genet

URL

Abstract Text

FANCJ/BRIP1 is an iron-sulfur (FeS) cluster-binding DNA helicase involved in DNA inter-strand cross-link (ICL) repair and G-quadruplex (G4) metabolism. Mutations in FANCJ are associated with Fanconi anemia and an increased risk for developing breast and ovarian cancer. Several cancer-associated mutations are located in the FeS domain of FANCJ, but how they affect FeS cluster binding and/or FANCJ activity has remained mostly unclear. Here we show that the FeS cluster is indispensable for FANCJ's ability to unwind DNA substrates in vitro and to provide cellular resistance to agents that induce ICLs. Moreover, we find that FANCJ requires an intact FeS cluster for its ability to unfold G4 structures on the DNA template in a primer extension assay with the lagging-strand DNA polymerase delta. Surprisingly, however, FANCJ variants that are unable to bind an FeS cluster and to unwind DNA in vitro can partially suppress the formation of replisome-associated G4 structures that we observe in a FANCJ knock-out cell line. This may suggest a partially retained cellular activity of FANCJ variants with alterations in the FeS domain. On the other hand, FANCJ knock-out cells expressing FeS cluster-deficient variants display a similar-enhanced-sensitivity towards pyridostatin (PDS) and CX-5461, two agents that stabilise G4 structures, as FANCJ knock-out cells. Mutations in FANCJ that abolish FeS cluster binding may hence be predictive of an increased cellular sensitivity towards G4-stabilising agents.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description
BRIP1	C283H	missense	loss of function	BRIP1 C283H lies within the helicase ATP-binding domain of the Brip1 protein (UniProt.org). C283H confers a loss of function to the Brip1 protein as demonstrated by reduced iron incorporation in an in vitro assay, and failure to rescue mitomycin C-induced cell death of Brip1 knockout cells in culture (PMID: 32542039).
BRIP1	C283R	missense	loss of function	BRIP1 C283R lies within the helicase ATP-binding domain of the Brip1 protein (UniProt.org). C283R confers a loss of function to the Brip1 protein as demonstrated by reduced iron incorporation in an in vitro assay, defective unwinding of D-loop DNA substrates and G-quadruplex (G4) DNA secondary structures, failure to suppress accumulation of replisome-associated G4 structures and rescue mitomycin C-induced cell death of Brip1 knockout cells in culture (PMID: 32542039).
BRIP1	C283S	missense	loss of function	BRIP1 C283S lies within the helicase ATP-binding domain of the Brip1 protein (UniProt.org). C283S confers a loss of function to the Brip1 protein as demonstrated by reduced iron incorporation in an in vitro assay, defective unwinding of D-loop DNA substrates and G-quadruplex (G4) DNA secondary structures, failure to suppress accumulation of replisome-associated G4 structures and rescue mitomycin C-induced cell death of Brip1 knockout cells in culture (PMID: 32542039).
BRIP1	L340F	missense	unknown	BRIP1 L340F lies within the helicase ATP-binding domain of the Brip1 protein (UniProt.org). L340F retains the ability to suppress replisome-associated G-quadruplex (G4) structures and to rescue mitomycin C-induced cell death of Brip1 knockout cells in culture, but results in reduced iron incorporation in an in vitro assay and decreased DNA helicase activity in culture (PMID: 32542039), and therefore, its effect on Brip1 protein function is unknown.
BRIP1	M299I	missense	unknown	BRIP1 M299I lies within the helicase ATP-binding domain of the Brip1 protein (UniProt.org). The functional effect of M299I is conflicting, as it has been reported to confer a loss of Brip1 DNA helicase activity in one study (PMID: 14983014), and to enhance DNA helicase activity in other studies (PMID: 32542039, PMID: 17145708).
BRIP1	R279Q	missense	loss of function	BRIP1 R279Q lies within the helicase ATP-binding domain of the Brip1 protein (UniProt.org). R279Q confers a loss of function to the Brip1 protein as demonstrated by reduced iron incorporation in an in vitro assay, and failure to rescue mitomycin C-induced cell death of Brip1 knockout cells in culture (PMID: 32542039).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRIP1 C283R	Advanced Solid Tumor	sensitive	CX-5461	Preclinical - Cell culture	Actionable	In a preclinical study, CX-5461 inhibited survival of transformed cells expressing BRIP1 C283R in culture (PMID: 32542039).	32542039
BRIP1 M299I	Advanced Solid Tumor	no benefit	CX-5461	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing BRIP1 M299I were not sensitive to CX-5461 induced growth inhibition in culture (PMID: 32542039).	32542039
BRIP1 K52R	Advanced Solid Tumor	sensitive	CX-5461	Preclinical - Cell culture	Actionable	In a preclinical study, CX-5461 inhibited survival of transformed cells expressing BRIP1 K52R in culture (PMID: 32542039).	32542039
BRIP1 A349P	Advanced Solid Tumor	sensitive	CX-5461	Preclinical - Cell culture	Actionable	In a preclinical study, CX-5461 inhibited survival of transformed cells expressing BRIP1 A349P in culture (PMID: 32542039).	32542039
BRIP1 del	Advanced Solid Tumor	sensitive	CX-5461	Preclinical - Cell culture	Actionable	In a preclinical study, CX-5461 inhibited survival of transformed cells with BRIP1 knocked out by CRISPR/Cas9 in culture (PMID: 32542039).	32542039
BRIP1 C283S	Advanced Solid Tumor	sensitive	CX-5461	Preclinical - Cell culture	Actionable	In a preclinical study, CX-5461 inhibited survival of transformed cells expressing BRIP1 C283S in culture (PMID: 32542039).	32542039
BRIP1 L340F	Advanced Solid Tumor	no benefit	CX-5461	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing BRIP1 L340F were not sensitive to CX-5461 induced growth inhibition in culture (PMID: 32542039).	32542039