8.11
ヌクレオチド除去修復
DNAの歪みと損傷
細胞は定期的に変異原、つまり DNA に損傷を与え、変異を引き起こす可能性のある環境中の要因にさらされています。 紫外線は最も一般的な突然変異原の 1 つであり、DNA にかなりの数の変化をもたらすと推定されています。 これらには、DNA の複製や転写をブロックする可能性がある構…
ヌクレオチド除去修復(NER)は、紫外線や化学発がん物質によって引き起こされるかさばるDNA損傷を修復します。
ピリミジン二量体などのこれらのかさばる病変は、DNAらせんを歪め、DNAの複製と転写を妨害します。
大腸菌では、修復タンパク質のUvrAとUvrBが複合体を形成し、ゲノムDNAの構造的病変をスキャンします。
病変に遭遇すると、UvrAは解離し、UvrBは歪んだDNAにしっかりと結合します。
次に、DNAに結合したUvrBは、エンドヌクレアーゼであるUvrCをリクルートし、病変の両側を切開します。
次に、UvrDヘリカーゼはDNAを巻き戻し、病変を運ぶ断片を切り取ります。
切除後、DNAポリメラーゼは新しい相補的ヌクレオチドでギャップを埋め、酵素DNAリガーゼは新しいDNAと古いDNAの間のギャップを塞ぎ、修復を完了します。
あるいは、能動的に転写するRNAポリメラーゼがかさばる病変に遭遇した場合、UvrBを病変部位に直接動員することができます。
これにより、転写共役ヌクレオチド除去修復が開始され、通常のNERと同様に進行して修復が完了し、転写が継続されます。
Q1: What types of DNA damage does nucleotide excision repair fix?
Nucleotide excision repair fixes bulky DNA lesions caused by UV radiation and chemical carcinogens, such as pyrimidine dimers. These lesions distort the DNA helix and interfere with DNA replication and transcription. If left unrepaired, they can cause mutations leading to cancer or disease depending on which DNA sequences are disrupted.
Q2: How do UvrA and UvrB proteins identify damaged DNA in prokaryotes?
In E. coli, UvrA and UvrB form a complex that scans genomic DNA for structural lesions. When the complex encounters a lesion, UvrA dissociates and UvrB binds tightly to the distorted DNA region. This recognition of physical aberrations allows the repair machinery to flag the damaged area for removal and repair.
Q3: What is the role of UvrC endonuclease in nucleotide excision repair?
UvrC is an endonuclease recruited by DNA-bound UvrB that makes incisions on either side of the lesion. These cuts allow the damaged DNA fragment to be excised from the strand. Following excision, DNA polymerase fills the gap with new complementary nucleotides, and DNA ligase seals the repair.
Q4: How does transcription-coupled nucleotide excision repair differ from regular NER?
Transcription-coupled NER is initiated when an actively transcribing RNA polymerase encounters a bulky lesion and directly recruits UvrB to the damage site. This alternative pathway proceeds identically to regular NER but is triggered by transcription blockage rather than routine DNA scanning, allowing repair and transcription to resume.
Q5: Why do eukaryotes require more proteins than prokaryotes for nucleotide excision repair?
Unlike prokaryotes, which use three proteins—UvrA, UvrB, and UvrC—eukaryotes employ more than a dozen proteins to regulate nucleotide excision repair. This increased complexity reflects the greater size and organization of eukaryotic genomes and the need for more sophisticated damage recognition and coordination mechanisms.
Q6: What happens when nucleotide excision repair genes are mutated in humans?
Mutations in the NER pathway cause diseases such as Xeroderma pigmentosum, associated with a 2000-fold increase in skin cancer incidence. XP patients are highly sensitive to UV exposure, developing severe burns after brief sunlight exposure, and often show premature aging and neurological abnormalities. Without functional repair, DNA damage accumulates, leading to abnormal cell death or cancerous tumors.
Q7: What is the final step after DNA polymerase fills the gap in nucleotide excision repair?
After DNA polymerase fills the gap with new complementary nucleotides, the enzyme DNA ligase seals the gap between the new and old DNA strands. This ligation completes the nucleotide excision repair process and restores the integrity of the DNA molecule.