DNA Repair

Presented By: Syayyida Muslimah (1509 100 012) Dinda Zahidah (1509 100 037) Wahyu Dewi Iftita (1509 100 707) Afina Dhuhaini (1510 100 004)

DNA is a highly stable molecule that replicates with amazing accuracy, but changes in DNA structure and errors of replication do occur. A mutation is defined as an inherited change in genetic information; the descendants may be cells produced by cell division or individual organisms produced by reproduction. Mutation is the source of all genetic variation, the raw material of evolution

Others: - UV radiation - Ionizing radiation - Cosmic rays - X-rays - Deamination - Etc.

Phenotypic Effects of Mutation

DNA Repair
DNA damage can be corrected by more than one pathway of repair. There are four general mechanisms of DNA repair : mismatch repair, direct repair, baseexcision repair, and nucleotide-excision repair.

Mismatch Repair

Type of damage repaired : Replication errors, including mispaired bases

Direct Repair
Direct-repair mechanisms do not replace altered nucleotides but instead change them back into their original (correct) structures.

Base-Excision Repair
In base-excision repair, modified bases are first excised and then the entire nucleotide is replaced.

Nucleotide-Excision Repair
Removes bulky DNA lesions that distort the double helix, such as pyrimidine dimers or large hydrocarbons attached to the DNA.

Presented By: Kelompok 1 : 1. Syayyida Muslimah (1509 100 012) 2. Dinda Zahidah (1509 100 037) 3. Wahyu Dewi Iftita (1509 100 707) 4. Afina Dhuhaini (1510 100 004)

DNA Damage & Genome Integrity

The mammalian genome is protected against genotoxic insults by a network of DNA damage response (DDR) Mechanisms triggered by the detection of DNA lesions through specific sensors. The multiprotein nucleotide excision repair (NER) system removes a wide variety of helix-destabilizing DNA lesions including those induced by UVirradiation. This broad substrate recognition is achieved by two distinct subpathways of NER

Global-Genome (GG) NER sub pathway

Is able to repair lesions throughout the entire genome by sensing the reduced rigidity of DNA imposed by the helix distortion.

Transcription-Coupled (TC) NER

specifically repairs DNA lesions in genes that block the actively transcribing RNA poly-merases II (RNAPIIo).

Global Genome NER (GG-NER)

Processing of UV-lesions by TC-NER

DNA Damage Signaling

The Replication Stress Response

ATR is the main sensor. Purposed function : Kinase activated by blockage of replication and perhaps transcription. Roles in normal replication activation of cell cycle checkpoints, DNA repair and apoptosis The ATR kinase orchestrates DNA repair, apoptosis, S-phase and G2 arrest via the Chk1, p53 and the Fanconi pathways

The Transcription Stress Response

SMG1, BRCA1 and ATR have potensial role in this stress The activated SMG1 kinase could then activate p53 by phosphorylating p53 on the ser15 site

The Chromatin Alteration Stress Response

The ATM kinase may monitor chromatin alterations

TC-NER deficiency : human disease and genome integity

Gejala - luka terbakar - banyak bintik-bintik di kulit - kulit tipis - mata sensitif pada sinar matahari Pengobatan Belum ditemukan obat untuk pigmentosum xeroderma. Tujuan utama dari pengobatan adalah untuk melindungi pasien dari paparan UV dan dengan demikian mencegah dampak buruk itu dapat memiliki pada kulit.

Xeroderma Pigmentosum (XP)

Penderita XP sangat sensitif terhadap radiasi ultraviolet (UV), termasuk UVA, UVB, dan UVC. Paparan matahari saja dapat menyebabkan kulit terbakar, kering dan sangat rentan terserang kanker kulit dan melanoma. Selain itu, mata penderita juga sangat sensitif pada cahaya yang juga rentan terserang kanker mata. Penyebab cacat dalam mekanisme perbaikan eksisi nukleotida Keterbelakangan mental, sindrom piramidal, neuropathia perifer; lebih parah sistem saraf pusat (SSP) gangguan diamati ketika mutasi terjadi pada situs DNA XPA Setelah penyinaran UV pada kultur sel, tidak ada peningkatan kelainan kromosom spontan dalam limfosit dari fibroblas, namun setelah paparan UV naik, trjd peningkatan jumlah pertukaran kromatid saudara (SCE) dan penyimpangan kromosom yang diamati (terutama kromatid-jenis kelainan); fibroblas mengekspresikan kepekaan meningkat menjadi mutagen kimia; tidak ada fitur sitogenetika berguna untuk diagnosis XP

Triochothiodystrophy
Adalah genodermatosis yg diturunkan scr resesif autosomal, ditandai oleh adanya iktiosis, rambut rapuh, penurunan intelektualitas, postur pendek, mikrosefali, penurunan kesuburan, dan mikrognatia. Pada TTD dijumpai keadaan fotosensitifitas terhadap sinar matahari. Adanya defisiensi sulfur menyebabkan rendahnya kadar sistein dan sistin protein sehingga trjd iktiosis, rambut dan kuku rapuh. Kelainan kulit tdk berhubungan dg malignasi seperti XP.

Adalah genodermatosis yg dirunkan scr resesif autosomal, ditandai hipersensitivitas seluler, postur pendek, degenerasi pigmentosa retina, kalsifikasi batang otak, kehilangan banyajklemak di wajah (birdheaded facial appearence). Terjadi penururunan fungsi neurologik akibat degenerasi lambat, seperti retadarsi mental, tuli, hidrosephalus, hiperreflexia. Defek genetik terjadi pada gen penyandi protein CSA dan CSB yg berperan utk identifikasi kerusakan DNA. efek : dwarfisme, kalsifikasi otak, peningkatan protein cairan otak, penurunan kognitif progesi, abnormalitas skeletal,.

Cockayne Syndrome (CS)

Any question???? Lets discuss!!!!!

Question
Sidratu 10-10: Daminasi sitosin urasil, gambarin donk mbak dinda strukturnya.. Hefdiyah 10-09 : sejauh manakah kerusakan yang tidak bisa diatasi hingga kemudian muncul berbagai penyakit?? *tergantung dari paparan UV (polutan penyebab damage) serta protein yg terlibat dalam repaaring DNA. Jk protein tidak dapat mengatasi maka terjadilah penyakit tersebut. Dadang 09-41 : mungkin g sih perubahan spesies karena perubahan struktur DNA?? *kalo dalam waktu dekat = g mungkin.