DNA damage-binding protein 2 is a protein that in humans is encoded by the ''DDB2''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

Structure

As indicated by Rapić-Otrin et al. in 2003, the ''DDB2'' gene is located on human chromosome 11p11.2, spans a region of approximately 24 – 26 kb and includes 10 exons. The DDB2 protein contains five putative

WD40 repeat The WD40 repeat (also known as the WD or beta-transducin repeat) is a short structural motif of approximately 40 amino acids, often terminating in a tryptophan-aspartic acid (W-D) dipeptide. Tandem copies of these repeats typically fold togeth ...

s (sequences of about 40

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

s that can interact with each other) positioned downstream from the second exon. The WD40 motif identified in DDB2 is characteristic of proteins involved in the recognition of chromatin proteins. The C-terminal region of DDB2 (a 48 kDa molecular weight protein) is essential for binding to DDB1 (a larger 127 kDa protein). Together, the two proteins form a UV-damaged DNA binding protein complex (UV-DDB).

Deficiency in humans

If humans have a mutation in each copy of their ''DDB2'' gene, this causes a mild form of the human disease

xeroderma pigmentosum Xeroderma pigmentosum (XP) is a genetic disorder in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light. Symptoms may include a severe sunburn after only a few minutes in the sun, freckling in sun ...

, called XPE. Patients in the XPE group have mild dermatological manifestations and are neurologically unaffected. Mutation in the ''DDB2'' gene causes a deficiency in

nucleotide excision repair Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals (e.g. intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single stranded DNA damage: Nucleo ...

of DNA. This deficiency is also mild, showing 40 to 60% of normal repair capability and a modest sensitivity to UV light in comparison to the sensitivities of cells defective in the other XP genes

XPA DNA repair protein complementing XP-A cells is a protein that in humans is encoded by the ''XPA'' gene. Function Nucleotide excision repair (NER) is a major pathway for repairing a variety of bulky DNA damages including those introduced by UV ir ...

, XPB, XPC,

XPD ''XPD'' is a spy novel by Len Deighton, published in 1981, and set in 1979, roughly contemporaneous with the time it was written. It concerns a plan by a group of former SS officers to seize power in West Germany, in which they intend to publi ...

, XPF and XPG.

Function

Binding to damaged DNA

As shown by Wittschieben et al., when DDB2 is in a complex with DDB1, forming the heterodimer DDB, this complex binds strongly to DNA containing one type of UV light-induced photoproduct he (6-4) photoproduct to DNA with an abasic site, to DNA containing mismatches without a covalent lesion, and to “compound” lesions containing both mismatches and lesions. The heterodimer DDB binds with intermediate strength to DNA containing another UV light-induced photoproduct (the cyclobutane pyrimidine dimer), and binds weakly to DNA that has no DNA damage. The DDB2 component of the heterodimer contains the specificity for binding to damaged DNA, since a heterodimer DDB complex containing amino acid substitutions in the DDB2 subunit, as found in XP-E patients, is very deficient in binding to damaged DNA. DDB1 and DDB2, each acting alone, do not bind DNA.

Chromatin remodeling

The packaging of eukaryotic DNA into

chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in ...

presents a barrier to all DNA-based processes that require recruitment of enzymes to their sites of action. To allow the critical cellular process of DNA repair, the chromatin must be relaxed. DDB2, in its heterodimeric complex with DDB1, and further complexed with the

ubiquitin ligase A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquit ...

protein CUL4A and with

PARP1 Poly DP-ribosepolymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly DP-ribosesynthase 1 is an enzyme that in humans is encoded by the ''PARP1'' gene. It is the most abundant of the PARP family of enzymes, accounting for 90% o ...

rapidly associates with UV-induced damage within chromatin, with half-maximum association completed in 40 seconds. The PARP1 protein, attached to both DDB1 and DDB2, then PARylates (creates a poly-ADP ribose chain) on DDB2 that attracts the DNA remodeling protein ALC1. Action of ALC1 relaxes the chromatin at the site of UV damage to DNA. This relaxation allows other proteins in the

pathway to enter the chromatin and repair the DNA damaged by the UV-induced presence of cyclobutane pyrimidine dimers.

Other functions

In 2015, Zhu et al. showed that DDB2 down-regulates the acetylation of lysine 56 in histone H3 (H3K56Ac) after UV-induced DNA damage through DDB2 interaction with

histone deacetylase Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...

s 1 and 2. Decreased acetylation of histones decreases transcription of associated genes in the DNA wrapped around the histones. In 2016, Zou et al. showed that DDB2 is involved in cell cycle arrest and

homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may be ...

al DNA repair after cells are subjected to ionizing radiation. In 2016, Christmann et al. showed that exposure of cells to the carcinogenic benzo(a)pyrene metabolite BPDE caused prompt and sustained upregulation of DDB2. This contributed to enhanced removal of BPDE

adduct An adduct (from the Latin ''adductus'', "drawn toward" alternatively, a contraction of "addition product") is a product of a direct addition of two or more distinct molecules, resulting in a single reaction product containing all atoms of all co ...

s from DNA. In 2017, Fantini et al. showed that DDB2, in association with

XRCC5 Ku80 is a protein that, in humans, is encoded by the ''XRCC5'' gene. Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway of DNA repai ...

and

XRCC6 Ku70 is a protein that, in humans, is encoded by the ''XRCC6'' gene. Function Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway ...

(otherwise known as

Ku80 Ku80 is a protein that, in humans, is encoded by the ''XRCC5'' gene. Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway of DNA rep ...

and

Ku70 Ku70 is a protein that, in humans, is encoded by the ''XRCC6'' gene. Function Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway ...

, which make up the Ku heterodimer), has

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

al activities. The DDB2/Ku effects on transcription are separate from the actions of the Ku heterodimer in

non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direct ...

DNA repair.

References

External links

GeneReviews/NIH/NCBI/UW entry on Xeroderma Pigmentosum