POLH gene cause Xeroderma Pigmentosum (XP)...

POLH gene shows 30+ mutations in the variant type of Xeroderma Pigmentosum (XP-V), which is characterized by increased sensitivity to UV rays from sunlight like the other forms of XP. However, XP-V do not associated with neurological abnormalities such as delayed development and hearing loss.

Most of the mutations in POLH gene prevent the production of any detectable DNA polymerase eta. As we know without DNA polymerase eta cells could not effectively replicate damaged DNA. Without DNA replication for damaged DNA, errors resulting from exposure to UV rays accumulate in the genes which control cell growth and division. Due to this damage, cell growth become uncontrollably fast resulting an increased risk of developing skin cancer in the sunlight exposed areas in the XP-V affected individual. 

Source: www.ghr.nlm.nih.gov

Function of the POLH gene...

The POLH gene provides instructions for making DNA polymerase eta. DNA polymerases are a group of enzymes which "read" sequences of DNA and use them as templates to produce new DNA. These enzymes play an important role in replication (copy) for cell division. DNA polymerase also play critical role in DNA repair.

The major function of DNA polymerase eta is to replicate damaged DNA from ultraviolet (UV) rays. Other DNA polymerases are unable to replicate DNA with the damage caused by ultra violet rays. When they reach a segment of damaged DNA, they get stuck and the replication process stalls. However, when DNA polymerase eta encounters damaged DNA, it skips over the abnormal segment and continues copying. This ‘Translesion Synthesis’ activity allows cells to tolerate some abnormalities created by UV exposure. Without this tolerance, unrepaired DNA damage would block DNA replication causing the cell death. Therefore, DNA polymerase eta plays an essential role in protecting cells from some of the effects of DNA damage.

DNA polymerase eta is a relatively "error-prone" polymerase. When it bypasses damaged DNA, it often inserts an incorrect DNA building block (nucleotide). This type of error results in a mutation in the replicated DNA.

Source: www.ghr.nlm.nih.gov

POLH gene … Location

Cytogenetic Location: 6p21.1

Molecular Location : Chromosome 6

base pairs 43,576,140 ~ 43,620,522

The POLH gene is located on the short (p) arm of chromosome 6 at position 21.1, precisely from base pair 43,576,140 to base pair 43,620,522.

POLH gene … Official name

Official Name: polymerase (DNA directed), eta.

Official Symbol: POLH 

Other Names:

Ê DNA polymerase eta

Ê FLJ16395

Ê FLJ21978

Ê POLH_HUMAN

Ê RAD30

Ê RAD30A

Ê RAD30 homolog A

Ê xeroderma pigmentosum variant type protein

Ê XPV

Ê XP-V

How mutations in ERCC3 gene cause XP?

A single mutation in the ERCC3 gene causes Xeroderma Pigmentosum (XP). The mutation replaces the amino acid phenylalanine with the amino acid serine at protein position 99 (written as Phe99Ser or F99S) which greatly reduces the ability of the TFIIH complex to repair damaged DNA. As a result, abnormalities accumulate in DNA causing cells to malfunction and eventually become cancerous or die. These problems with DNA repair process cause people with XP to be extremely sensitive to UV rays from sunlight. When UV rays damage genes that control cell growth and division, cells can grow uncontrollably too fast, increasing the risk of developing cancer in XP patient. These cancers occur most frequently in areas of the body which are exposed to the sun such as the skin and eyes.

In addition to sun sensitivity, XP is sometimes associated with progressive neurological abnormalities but in affected individuals with Phe99Ser mutation have mild neurological abnormalities including hearing loss and poor coordination. Studies suggest that the neurological abnormalities associated with this condition result from a buildup of DNA damage, though the brain is not exposed to UV rays. Researchers suspect that other factors can damage DNA in nerve cells. It is unclear why some people with XP develop neurological abnormalities and others do not.

Source: www.ghr.nlm.nih.gov

Normal function of the XPB/ERCC3 gene

The ERCC3 gene helps in making a protein called XPB. XPB is an essential subunit of a group of proteins known as the general transcription factor IIH (TFIIH) complex. The TFIIH complex has two major functions:

          I.      It involves in a process of gene transcription

        II.      It helps repair damaged DNA.

Gene transcription is the first step in protein production. By controlling gene transcription, the TFIIH complex helps regulate the activity of many different genes. Research suggest that the XPB protein works together with XPD, another protein in the TFIIH complex that is produced from the ERCC2 gene, to initiate gene transcription.

The TFIIH complex also plays an important role in repairing damaged DNA, which can be damaged by ultraviolet (UV) rays from the sun and by toxic chemicals, radiation and unstable molecules called free radicals. As we already know that DNA damage occurs frequently, but normal cells usually fix the damage through nucleotide excision repair (NER) mechanism before it can cause problems. As part of this repair mechanism, the TFIIH complex unwinds the section of double-stranded DNA that surrounds the damage. Studies suggest that the XPB protein may act as a wedge, holding open the two strands of DNA so other proteins can snip out (excise) the abnormal section and replace the damaged area with the correct DNA.

Source: www.ghr.nlm.nih.gov

XPB/ERCC3 … Location

Cytogenetic Location: 2q21

Molecular Location: Chromosome 2

                           base pairs 127,257,289 ~ 127,294,175

The ERCC3 gene is located on the long (q) arm of chromosome 2 at position 21 from base pair 127,257,289 to 127,294,175 

XPB/ERCC3 ..... Official Name

Official Name: excision repair cross-complementation group 3

Official Symbol: ERCC3

Other Names:

Ê  basic transcription factor 2 89 kDa subunit

Ê  BTF2

Ê  BTF2 p89

Ê  DNA excision repair protein ERCC-3

Ê  DNA repair protein complementing XP-B cells

Ê  ERCC3_HUMAN

Ê  excision repair cross-complementing rodent repair deficiency, complementation group 3

Ê  excision repair cross-complementing rodent repair deficiency, complementation group 3 (xeroderma pigmentosum group B complementing)

Ê  GTF2H

Ê  RAD25

Ê  TFIIH 89 kDa subunit

Ê  TFIIH basal transcription factor complex 89 kDa subunit

Ê  TFIIH basal transcription factor complex helicase XPB subunit

Ê  TFIIH p89

Ê  xeroderma pigmentosum, complementation group B

Ê  xeroderma pigmentosum group B-complementing protein

Ê  XPB

How XPD/ ERCC2 cause XP .....

More than 24 mutations in the XPD/ERCC2 gene have been identified in people with Xeroderma Pigmentosum (XP). In USA, mutations in XPD gene are the second most common cause of XP.

The XPD/ERCC2 gene mutations prevent the TFIIH complex from repairing damaged DNA effectively. As a result, abnormalities accumulate in DNA, causing cells to malfunction and eventually the cells become cancerous or die. These problems with DNA repair cause people with XP to be extremely sensitive to UV rays from sunlight. When UV rays damage genes which control cell growth and division, cells can grow too fast and in an uncontrolled way. As a result, people with XP have a greatly increased risk of developing cancer. These cancers occur most frequently in areas of the body exposed to the sun such as the skin and eyes.

When XP is caused by XPD/ERCC2 gene mutations, it is often associated with progressive neurological abnormalities such as hearing loss, poor coordination, difficulty walking, movement problems, loss of intellectual function, difficulty swallowing & talking, seizures etc. The neurological abnormalities are thought to result from a buildup of DNA damage, although the brain is not exposed to UV rays. Researchers suspect that other factors damage DNA in nerve cells. It is unclear why some people with XP develop neurological abnormalities while others do not.

Source: www.ghr.nlm.nih.gov

Normal function of the XPD / ERCC2 gene

The ERCC2 gene provides instructions for making a protein called XPD. This protein is an essential subunit of a group of proteins known as the general transcription factor IIH (TFIIH) complex. The TFIIH complex has two major functions:

1) It is involved in a process called gene transcription

2) It helps repairing damaged DNA.

Gene transcription is the first step in protein production. By controlling gene transcription, the TFIIH complex helps regulate the activity of many different genes. The XPD protein appears to stabilize the TFIIH complex. Studies suggest that the XPD protein works together with XPB, another protein in the TFIIH complex that is produced from the ERCC3 gene, to initiate gene transcription.

The TFIIH complex also plays an important role in repairing damaged DNA, which can be damaged by ultraviolet (UV) rays from the sun and by toxic chemicals, radiation, and unstable molecules called free radicals. DNA damage occurs frequently but normal cells are usually able to fix it before it can cause problems ¾ with the help of nucleotide excision repair (NER) mechanism. As part of this repair mechanism, the TFIIH complex separates the section of double-stranded DNA which surrounds the damage. The XPD protein helps with this process by acting as a helicase, which is an enzyme that attaches to particular regions of DNA and temporarily unwinds the two spiral strands. Once the damaged region has been exposed, other proteins excise the abnormal section and replace the damaged area with the correct DNA.

Source: www.ghr.nlm.nih.gov

XPD/ ERCC2 ... Location

Cytogenetic Location: 19q13.3

Molecular Location: Chromosome 19

                           base pairs 45,351,390 ~ 45,370,586

   

The XPD/ ERCC2 gene is located on the long (q) arm of chromosome 19 at position 13.3 from base pair 45,351,390 ~ 45,370,586.

XPD / ERCC2 ..... Official Name

Official Name:  Excision repair cross-complementation group 2

Official Symbol: ERCC2 

Other Names:

Ê basic transcription factor 2 80 kDa subunit

Ê BTF2 p80

Ê COFS2

Ê CXPD

Ê DNA excision repair protein ERCC-2

Ê DNA repair protein complementing XP-D cells

Ê EM9

Ê ERCC2_HUMAN

Ê excision repair cross-complementing rodent repair deficiency, complementation group 2

Ê MAG

Ê MGC102762

Ê MGC126218

Ê MGC126219

Ê TFIIH

Ê TFIIH 80 kDa subunit

Ê TFIIH basal transcription factor complex 80 kDa subunit

Ê TFIIH basal transcription factor complex helicase subunit

Ê TFIIH p80

Ê TTD

Ê xeroderma pigmentosum complementary group D

Ê xeroderma pigmentosum group D-complementing protein

Ê XPD

How XPC gene related to health cause XP .....

Xeroderma Pigmentosum (XP) is caused by mutations in the XPC gene. More than 40 mutations in the XPC gene have been found to cause Xeroderma Pigmentosum. Mutations in this gene are the most common cause of this disorder in the United States and Europe.

Most XPC gene mutations prevent the production of any XPC protein. A loss of this protein keeps cells from repairing DNA damage normally. As a result, abnormalities accumulate in DNA, causing cells to malfunction and eventually to become cancerous or die. These problems with DNA repair cause people with XP to be extremely sensitive to UV rays from sunlight. When UV rays damage genes that control cell growth and division, cells can grow too fast in an uncontrolled way. As a result, people with XP  have a greatly increased risk of developing cancer. These cancers occur most frequently in areas of the body that are exposed to the sun, such as the skin and eyes.

Unlike some of the other forms of Xeroderma Pigmentosum (XP), when the disorder is caused by mutations in the XPC gene it is generally not associated with neurological abnormalities (such as delayed development and hearing loss). It is unclear why some people with XP develop neurological abnormalities and others do not.

Source: www.ghr.nlm.nih.gov

Normal Function of the XPC gene …..

The XPC gene provides instructions for making a protein which is involved in repairing damaged DNA ¾ DNA can be damaged by ultraviolet (UV) rays from the sun and by toxic chemicals, radiation, and unstable molecules called free radicals.

As we already know that DNA damage occurs frequently, but normal cells are usually able to fix it before it can cause problems ¾ one of the major mechanisms to fix DNA is known as nucleotide excision repair (NER). The XPC protein starts this repair process by detecting DNA damage. Then a group (complex) of other proteins unwinds the section of DNA where the damage has occurred, snip out (excise) the abnormal section and replace the damaged area with the correct DNA.

Studies suggest that the XPC protein may have additional roles in DNA repair and in other cell activities. Very less is known about the proposed functions of the XPC protein.

XPC ... Location

Cytogenetic Location: 3p25

Molecular Location: Chromosome 3

                           base pairs 14,145,146 ~ 14,178,671

The XPC gene is located on the short (p) arm of chromosome 3 at position 25 from base pair 14,145,146 ~ 14,178,671.

Source: www.ghr.nlm.nih.gov 

XPC ... Official Name

Official Name:  Xeroderma Pigmentosum, complementation group C

Official Symbol: XPC

Other Names:

Ê RAD4

Ê Xeroderma pigmentosum group C-complementing protein

Ê XP3

Ê XPCC

Ê XPC_HUMAN