Mechanistic Insight into Site-Restricted Monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI

Arno F. Alpi; Paul E. Pace; M. Madan Babu; Ketan J. Patel

doi:10.1016/j.molcel.2008.12.003

Mechanistic Insight into Site-Restricted Monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI

Arno F. Alpi, Paul E. Pace, M. Madan Babu, Ketan J. Patel (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

163 Citations (Scopus)

Abstract

A key step in the Fanconi anemia (FA) tumor suppressor pathway is the site-specific monoubiquitination of the FANCD2 protein. Genetic studies indicate that this crucial modification requires eight known FA gene products and the E2-conjugating enzyme Ube2t. Here, we minimally reconstitute this monoubiquitination reaction with Ube2t and the FANCL protein, revealing that monoubiquitination is stimulated by a conserved RWD-like domain in FANCL. Furthermore, addition of the FANCI protein enhances monoubiquitination and also restricts it to the in vivo substrate lysine residue on FANCD2. This work therefore establishes a system that provides mechanistic insight into the functions of FANCL and FANCI in the catalysis of FANCD2 monoubiquitination.

Original language	English
Pages (from-to)	767-777
Number of pages	11
Journal	Molecular Cell
Volume	32
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2008.12.003
Publication status	Published - 26 Dec 2008

Keywords

ANEMIA CORE COMPLEX
DNA-DAMAGE RESPONSE
CROSS-LINK REPAIR
PATHWAY
PROTEIN
IDENTIFICATION
DOMAIN
UBIQUITINATION
CHROMATIN

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title = "Mechanistic Insight into Site-Restricted Monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI",

abstract = "A key step in the Fanconi anemia (FA) tumor suppressor pathway is the site-specific monoubiquitination of the FANCD2 protein. Genetic studies indicate that this crucial modification requires eight known FA gene products and the E2-conjugating enzyme Ube2t. Here, we minimally reconstitute this monoubiquitination reaction with Ube2t and the FANCL protein, revealing that monoubiquitination is stimulated by a conserved RWD-like domain in FANCL. Furthermore, addition of the FANCI protein enhances monoubiquitination and also restricts it to the in vivo substrate lysine residue on FANCD2. This work therefore establishes a system that provides mechanistic insight into the functions of FANCL and FANCI in the catalysis of FANCD2 monoubiquitination.",

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author = "Alpi, {Arno F.} and Pace, {Paul E.} and Babu, {M. Madan} and Patel, {Ketan J.}",

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T1 - Mechanistic Insight into Site-Restricted Monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI

AU - Alpi, Arno F.

AU - Pace, Paul E.

AU - Babu, M. Madan

AU - Patel, Ketan J.

PY - 2008/12/26

Y1 - 2008/12/26

N2 - A key step in the Fanconi anemia (FA) tumor suppressor pathway is the site-specific monoubiquitination of the FANCD2 protein. Genetic studies indicate that this crucial modification requires eight known FA gene products and the E2-conjugating enzyme Ube2t. Here, we minimally reconstitute this monoubiquitination reaction with Ube2t and the FANCL protein, revealing that monoubiquitination is stimulated by a conserved RWD-like domain in FANCL. Furthermore, addition of the FANCI protein enhances monoubiquitination and also restricts it to the in vivo substrate lysine residue on FANCD2. This work therefore establishes a system that provides mechanistic insight into the functions of FANCL and FANCI in the catalysis of FANCD2 monoubiquitination.

AB - A key step in the Fanconi anemia (FA) tumor suppressor pathway is the site-specific monoubiquitination of the FANCD2 protein. Genetic studies indicate that this crucial modification requires eight known FA gene products and the E2-conjugating enzyme Ube2t. Here, we minimally reconstitute this monoubiquitination reaction with Ube2t and the FANCL protein, revealing that monoubiquitination is stimulated by a conserved RWD-like domain in FANCL. Furthermore, addition of the FANCI protein enhances monoubiquitination and also restricts it to the in vivo substrate lysine residue on FANCD2. This work therefore establishes a system that provides mechanistic insight into the functions of FANCL and FANCI in the catalysis of FANCD2 monoubiquitination.

KW - ANEMIA CORE COMPLEX

KW - DNA-DAMAGE RESPONSE

KW - CROSS-LINK REPAIR

KW - PATHWAY

KW - PROTEIN

KW - IDENTIFICATION

KW - DOMAIN

KW - UBIQUITINATION

KW - CHROMATIN

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U2 - 10.1016/j.molcel.2008.12.003

DO - 10.1016/j.molcel.2008.12.003

M3 - Article

C2 - 19111657

SN - 1097-2765

VL - 32

SP - 767

EP - 777

JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -

Mechanistic Insight into Site-Restricted Monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI

Abstract

Keywords

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